ABSTRACT

Metabolic bone disease (MBD) encompasses a heterogeneous group of disorders having a diverse spectrum of manifestations varying from asymptomatic to florid. MBD is prevalent globally, but certain unique features characterize those occurring in the tropics. Dietary deviations, including malnutrition, environmental influences, genetic factors, and limited access to healthcare, modify the tropical presentation of MBD. Osteoporosis remains the most prevalent MBD in the tropics. Anti-osteoporotic agents are widely available, but the compliance and follow-up are poor. Fracture liaison services are gaining importance to address the low rates of patient work-up and treatment following a fracture. Though the tropics have long been plagued with communicable diseases, there is a recent increase in noncommunicable lifestyle diseases and obesity, which are major risk factors for sarcopenia. A significant subset of adults over the age of 65 years have sarcopenia complicated by obesity and are at risk of synergistic complications from both obesity and sarcopenia. "Thin-fat obesity" or "sarcopenic obesity," also known as normal weight obesity, is a recognized phenotype in South Asia, with a comparable risk for cardiometabolic disease as obesity. In addition to osteosarcopenia, other MBDs, such as rickets and osteomalacia, still prevail in tropical countries. Symptomatic hyperparathyroidism is still seen in tropical countries, unlike the West, where asymptomatic hyperparathyroidism is more common. Skeletal fluorosis, an MBD caused by chronically ingesting excess fluoride, can be asymptomatic, but a broad range of manifestations can occur, such as diffuse skeletal pain, limited mobility, osteopenia, and ossification of ligaments and interosseous membranes. The oral cavity can be a window to other MBDs like dental fluorosis in the tropics. Several infective disorders that can affect bones and joints, such as tuberculosis, leprosy, treponemal and fungal infections are prevalent in the tropics and should be considered in the differential diagnosis of tropical MBD.

INTRODUCTION

Metabolic bone disease (MBD) encompasses a diverse variety of bone and mineral metabolism disorders that often pose diagnostic and therapeutic challenges. The manifestations might differ in the tropics because of nutritional, environmental, and genetic factors. The presentation is often late and severe because of limited access to healthcare facilities and a lack of routine screening practices. Osteoporosis, the most prevalent MBD globally, is also widespread in the tropics. Despite ample sunlight exposure, vitamin D deficiency continues to be common. Certain conditions, such as fluorosis, lead, and cadmium toxicity, and infective skeletal disorders e.g., tuberculosis, syphilis, and leprosy, are unique to these regions. The altered presentation of the globally prevalent MBDs and conditions specific to the tropics have been highlighted here.

OSTEOPOROSIS IN THE TROPICS

Osteoporosis is the most common MBD globally and in tropical countries. Different studies in the South Asian region have suggested the prevalence of osteoporosis to be 30 to 50% among postmenopausal women and up to 20% in men above 50 years (1, 2). With increasing life expectancy in tropical countries, this prevalence will likely increase in the coming years. Several factors contribute to the high frequency and unique features of osteoporosis in tropical countries. These are summarized in table 1.

Despite the high mortality from hip fractures and the immense costs associated with its management, awareness about osteoporosis and its screening is poor among patients and physicians. In a study from southern India, 60% of postmenopausal women (n =302, mean age of 58 years) lacked knowledge of osteoporosis. In another study among general practitioners (n = 220), the total mean score on awareness was only 22% (1, 4).

Given the limitation of the diagnostic facilities, simple, cost-effective screening tools have been validated for use in the tropics. These may range from simple clinical findings like dental health assessment to more comprehensive evaluation through the FRAX tool. Easy-to-follow clinical practice guidelines have been developed that help manage patients with osteoporosis despite the above-mentioned constraints (5, 6).

Given poor dietary calcium intake and low levels of 25-hydroxyvitamin D [25(OH)D] despite abundant sunlight, adequate calcium and vitamin D is an essential component of osteoporosis management in these patients. Anti-osteoporotic agents are widely available, but compliance and follow-up are poor. The usage of bone turnover markers is still emerging and may evolve as a cost-effective tool. Moreover, strategies such as the fracture liaison service (FLS) will be helpful to enhance care for secondary prevention of fragility fractures (7).

DISORDERS OF BONE MINERAL METABOLISM IN THE TROPICS

Rickets And Osteomalacia

Rickets and osteomalacia are also prevalent in tropical countries. In children, the prevalence of nutritional calcipenic rickets has decreased significantly but remains the usual cause of a rachitic presentation. It’s a bit paradoxical for tropical countries with abundant sunlight to have a high occurrence of vitamin D deficiency. Though rare, the genetic causes of calcipenic and phosphopenic rickets may be more frequent in specific pockets where consanguinity is practiced.

Like children, dietary deficiency is the usual etiology of osteomalacia in adults. However, certain acquired causes are common and must be ruled out. These include renal tubular dysfunction caused by heavy metal exposure, often from native medications. Moreover, Fanconi syndrome can result from certain drugs used to treat infectious disorders. For example, tenofovir used to treat hepatitis B can lead to proximal renal tubular acidosis. The rampant use of glucocorticoids in different over-the-counter products enhances the risk of glucocorticoid-induced osteomalacia. Furthermore, a gradual increase in chronic kidney disease (CKD) in tropical countries, is leading to a higher incidence of renal osteodystrophy (8).

Vitamin D deficiency in the tropics is widespread and ranges from 40 to 80%. Several postulates have been proposed to explain the lower vitamin D levels despite adequate sunlight. These include increased melanin in the skin, predominant indoor habits, and lack of vitamin D fortification. The relatively higher amount of fat for a given body mass index affects the redistribution of vitamin D. Lastly, air pollution in certain metropolitan cities reduces exposure to sunlight. Other causes of osteomalacia in tropical countries include renal tubular dysfunction and acquired hypophosphatemic disorders, covered in the “Diseases of Bone and Mineral Metabolism” section in Endotext.

Hyperparathyroidism

Parathyroid disorders could be classified as primary – wherein the parathyroid gland is diseased and secretes excessive parathyroid hormone (PTH), or secondary – where excess PTH secretion occurs as a compensatory response to systemic conditions such as vitamin D deficiency, chronic kidney disease, etc. The third variety, tertiary hyperparathyroidism, is characterized by the autonomous transformation of the parathyroid gland during prolonged secondary PTH hypersecretion (9).

Hyperparathyroidism differs in clinical presentation in tropical countries and often manifests as florid disease. Parathyroid disorders are usually slowly evolving, and overt skeletal defects are declining as more facilities start to screen for calcium in the tropics routinely. Thus, the prevalence of asymptomatic disease is gradually increasing (10). The salient differences in tropical countries are summarized in table 2.

Scurvy

Nutritional deficiencies are rare in the developed world but are observed in tropical countries. Vitamin C deficiency is a rare cause of MBD but should be considered while evaluating patients with suggestive symptoms and radiological features. It may affect the bone and joints, but initial diagnosis is often missed due to nonspecific symptoms and signs. Initial manifestations include irritability, decreased appetite, and delayed development followed by a pseudo-paralysis-like state wherein the patient lies still with little movement because of generalized pain, most apparent in bones due to subperiosteal hemorrhages. Swelling may be noted along the shaft of long bones.

Radiological changes in the long bones, particularly around the knee, are peculiar to scurvy. The bones are often fragile, with bone mineral density (BMD) in the osteopenic range. Fracture healing is often associated with large callus formation. Moreover, the epiphyses and periosteum are easily detachable due to the sub-periosteal bleeding. A classical feature on radiography known as the Wimberger ring is a circular, opaque radiologic shadow surrounded by a white line, seen in the growth centers around the epiphysis, as shown in Figure 1. The cortical bone in vitamin C deficiency is characterized by thinning, often described as a “pencil-point” cortex.

Figure 1. Illustration of the radiological features of scurvy.

The physis exhibits the Frankel line, characterized by thickening and sclerosis accompanied by a subjacent zone of lucency. The physeal thickening is known as a Frankel line, and the adjacent lucent zone on its diaphyseal side is the Trümmerfeld zone or the scurvy line. Metaphyseal “beaks” and transverse lines of increased or decreased opacity may be seen in scurvy. The “beaks,” known as Pelkan spurs, are associated with healing fractures of the Trümmerfeld zone at the periphery of the site of calcification. Costochondral junctions of the first six or eight thoracic ribs may be expanded; this change may be related to fracturing of the zone of provisional calcification during normal respiration. The costochondral junctions are rounded and appear smooth, knobby, and steplike. The enlargement of the costochondral junctions simulates findings seen in rickets but is often painful.

The diagnosis of scurvy is based on a combination of clinical and radiographic findings. A dietary history suggestive of poor vitamin C intake for at least one to three months is required for the appearance of clinical symptoms. Unlike other MBDs, accurate laboratory measurement of vitamin C levels is unreliable as it does not reflect the tissue levels. Healing occurs rapidly with the oral administration of 100 to 200 mg/d of vitamin C (11).

Paget’s Disease Of The Bone

Paget’s disease of the bone is a rare disorder in the tropics compared to the temperate regions but has been reported in certain pockets, especially in southern India. The overall global prevalence seems to be declining. Several viruses, such as paramyxoviridae, respiratory syncytial virus, canine distemper virus, and measles virus, have been linked to its etiopathogenesis. Given the high prevalence of many of these viruses in the tropics, the tropical connection of Paget’s disease has received renewed attention.

An underlying genetic etiology also predisposes to a higher occurrence in consanguineous populations. Due to the nonspecific symptoms, poor awareness among treating physicians, and limited availability of bone scans, the diagnosis is often missed. Thus, its true prevalence is unlikely to be determined. In a study from southern India, the mean age was 60 years in a cohort of 48 patients. It was reported predominantly in men (65%), and about one-fifth of them were asymptomatic. Among the symptomatic patients, 87% have polyostotic involvement. Sixty-nine percent of them were treated with zoledronic acid, and all achieved remission immediately after therapy (12).

Renal Tubular Disorders (Acquired & Genetic)

Different varieties of genetic and acquired renal tubular acidosis (RTA) are known to occur in the tropics. Specifically, the SLC4A1 (solute carrier family 4 A1) gene mutation-induced dysfunction of the erythroid and kidney isoforms of anion exchanger 1 (AE1 or band 3) causes distal RTA in some areas of the tropics. The mutation is prevalent in Thailand, Malaysia, the Philippines, and Papua New Guinea. The inheritance is autosomal recessive and can result from either homozygous or compound heterozygous SLC4A1 mutations (13). Wilson’s disease, sickle cell anemia, and medullary sponge kidney are the other genetic causes of RTA more frequently encountered in regions where consanguinity is common.

Among the acquired causes, several drugs have been implicated in the pathogenesis of RTA. Some of these are used in managing common infective disorders in tropical countries, for example, tenofovir, for treating hepatitis B. One study reported lower bone mass (12.3%) in patients with hepatitis B on tenofovir compared to those not on the drug or those without hepatitis B (8). Among other acquired causes of RTA, amphotericin B, analgesic abuse, recurrent urinary tract infection, and hyperparathyroidism have been commonly reported in some tropical countries.

INFECTIVE DISORDERS ASSOCIATED WITH METABOLIC BONE DISEASE

Several infective disorders affect bones and joints, causing debilitating disease. Given the high incidence of infectious conditions in the tropical countries, the concurrence of bone lesions is expected. 

Tuberculosis

Tuberculosis is an unusual cause of bony lesions, but immunocompromised states such as human immunodeficiency virus (HIV) infection and diabetes increase the risk. Spine involvement can present insidiously, with progressive back pain in endemic areas, especially when consecutive thoracic vertebrae are affected with relative disc preservation. Paravertebral and epidural soft tissue lesions may present as a cold abscess. Atypical tubercular osteoarticular manifestations involving the extraspinal skeleton, a prosthetic joint, or the trochanteric area, and nontuberculous mycobacterial infections should raise suspicion for immunocompromised states. Surgery combined with prolonged antitubercular therapy is indicated for neurological manifestations or deformities and provides satisfactory results in most cases. Because of the increasing resistance to antitubercular treatment, appropriate culture and sensitivity testing should be ordered whenever indicated (14).

Leprosy

Mycobacterium leprae primarily affects the skin and nerves. Effective antimicrobial therapy has improved outcome in the acute stage of infection. However, long-term sequelae such as foot drop are not unusual if the diagnosis is delayed. Ineffective penetration of antimycobacterial therapy into neural tissue can predispose to continued nerve damage and result in Charcot’s neuroarthropathy. Other chronic effects include male osteoporosis and hypogonadism. Testicular atrophy following invasion by Mycobacterium leprae have caused osteoporosis in a few cases (15).

Treponemal Diseases

The spirochete Treponema pallidum causes syphilis. Earlier published series have described three broad types of skeletal malformations. They include - group I: metaphyseal dystrophy, group II: osteitis-like dystrophy, and group III: periosteal dystrophy. Advances in case detection, treatment, and prevention have significantly lowered the incidence of the disease and its associated complications (16). Contrary to the earlier view that the malformations are inflammatory, newer evidence suggests that dystrophic changes are responsible. In a series of 55 cases, the most frequent osseous findings were metaphysitis, zone of rarefaction, periostitis, disorganized metaphysis, bone erosion, and Wimberger sign. The bones commonly affected were the long bones such as radius, ulna, tibia, femur, humerus, and fibula (17).

Fungal Infection

Osteoarticular mycoses are uncommon in clinical practice and Aspergillus and Candida are the organisms involved usually. Dimorphic fungi such as Histoplasma, Blastomyces, Coccidiosis, and Paracoccidiodes can affect the bones in endemic areas. They occur predominantly in immunocompetent hosts and are characterized by hematogenous dissemination. The natural history is typically indolent but occasionally the organisms behave virulently.

While mucormycosis is highly aggressive and destructive in the lung, sinuses, and brain, it is relatively indolent in the bone. Mucormycosis can affect any bones and joints without specific predilection for any particular site. Most cases occur from direct inoculation of the bone rather than through systemic seeding. Osteoarticular mucormycosis can sometimes necessitate bony amputation to prevent the nidus from spreading through the systemic circulation. A high index of suspicion, early diagnosis, and intensive treatment are the key to successful management (18).

CHEMICAL AND TOXIN-RELATED DISORDERS IN TROPICAL COUNTRIES

Skeletal Fluorosis

Skeletal fluorosis is caused by chronically ingesting excess fluoride, usually from natural sources. Skeletal fluorosis can be asymptomatic, but a broad range of manifestations, including diffuse skeletal pain, limited mobility, osteopenia, and ossification of ligaments and interosseous membranes, are known to occur. The severity of the disease depends on the amount and duration of fluoride exposure. The portal of entry is oral, and after absorption from the gastrointestinal tract, it is deposited in the skeleton, where it has a half-life of more than seven years. Incorporation of the fluoride in the hydroxyapatite crystal affects bone strength, and influences bone remodeling through the Runt-related transcription factor 2 (Runx2) and receptor activator of nuclear factor kappa-В ligand (RANKL). This alters the expression of osteocalcin and osteoprotegerin with resultant increased osteoblastic activity (19).

The usual clinical features are dental mottling, bony pains, chronic fatigue, joint stiffness with restricted range of motion, flexion contractures, radiculo-myelopathy, and increased fracture risk. The diagnosis is based on a high index of clinical suspicion and confirmed by a 24-hour estimation of the urinary fluoride level. There is no effective treatment for established skeletal fluorosis. Management consists of symptomatic therapy with analgesics and provision of adequate calcium and vitamin D. Decompressive laminectomy may be performed to relieve neurological deficits due to spine involvement. Identifying the source of high fluoride intake, defluoridation, or changing the water source helps prevent worsening.

Lead Toxicity And Its Effect On Bone

Lead toxicity remains a substantial public health problem globally and in tropical countries. Bone is a major reservoir of lead in both adults and children, accounting for 75-90% of the total body lead. The accumulated lead can gradually be released to other soft tissues and pathological sites. Bone lead accrual occurs after both environmental and occupational exposure. It is a marker of past lead exposure with a half-life of 20 years and thus increases gradually with age. (20)

Lead exerts a detrimental effect by reducing osteocalcin production and inhibiting alkaline phosphatase activity in osteoblasts. Lead suppresses type II and type X collagen expression in chondrocytes and alters growth factors and second messenger signaling responses during chondrocyte maturation. Lead stimulates the osteoclasts to enhance bone resorption. Strict vigilance and robust policy decisions to decrease lead exposure will improve skeletal health in the tropics.

Cadmium Toxicity And Metabolic Bone Disease

Exposure to cadmium is associated with kidney, bone, and cardiovascular disorders. Like lead, cadmium is stored in the renal tissue for many years (half-life 10–30 years), which could result in renal tubular dysfunction, glomerular damage, and renal failure. A population-based study among postmenopausal women showed a clear link between a high burden of cadmium and low BMD (21). There are two proposed mechanisms for bone loss; a direct action on bone cells and an indirect action on the kidney resulting in phosphate and calcium excretion. In vitro studies have demonstrated that cadmium can increase the RANKL expression, tartarate-resistant acid phosphatase (TRAP) activity, and formation of TRAP-positive cells in the presence of RANKL, resulting in increased osteoclastic activity.

In tropical countries, silversmiths have exposure to cadmium in the absence of personal protective equipment. Case reports of exposure to cadmium and consequent renal osteodystrophy have been reported (22).

Alcohol And Metabolic Bone Disease

Alcohol consumption can, directly and indirectly, affect bone health. The mechanisms are summarized in Figure 2. In a study by Peris et al., vertebral fractures were observed in 36% of those consuming alcohol chronically, but only 6.5% had BMD below the fracture threshold. Thus chronic alcohol consumption may lead to a higher propensity for vertebral fractures without impacting the BMD (23). The evaluation and treatment would depend upon the clinical profile.

Figure 2. Impact of chronic alcohol consumption on metabolic bone disease.

NEPHROLITHIASIS IN TROPICS

Renal stone disease is a common problem worldwide. The prevalence and composition of renal stones differ according to country, climate, and culture (24). Conforming to that trend, renal stone diseases in tropical countries exhibit some unique features. The usual constituents of stones include calcium oxalate, calcium phosphate, uric acid, cysteine, struvite, or a mixture of these. In many tropical countries, local factors influence the composition of the stone. Nephrolithiasis, in general, has been reviewed elsewhere in endotext.org (25).

The prevalence of renal stone disease in older reports ranged from 7 to 13% in North America, 5–9% in Europe, and 1–5% in Asia (26). The lower frequency in Asia could be partially from underreporting. Recent findings demonstrate that the incidence of renal stones has increased by 48.5% in the last three decades across the globe (26, 27). The age-standardized incidence rate (ASIR) was greater in countries with high, middle, and low-middle sociodemographic index (SDI) than in low SDI regions. Some African countries, such as Madagascar, South Sudan, and Burundi, had a lower incidence of renal stones (27). An increased oxalate-degrading bacteria count in the gut of black South Africans could be a possible explanation (28).

The tropical region of Asia, spanning West Asia, South Asia, and Southeast Asia, constitutes a stone-forming belt with high prevalence (5% to 19.1%) (29). Higher temperatures and sunlight exposure increase the risk in these regions (30). Similar trends are also described in Latin America (31). Globally, the peak incidence of nephrolithiasis occurs between 50 to 70 years, though in Asians, the maximum incidence is around 30 years. Males are affected more often globally and in Asia (27, 29).

Unique Aspects In Tropics

TROPICAL CLIMATE AND STONE FORMATION

Higher ambient temperature and low humidity in the tropics increase fluid loss through sweating. Urinary concentration increases as compensation, and relatively insoluble salts such as calcium oxalate and urates tend to precipitate and serve as foci of stone formation. Sweating-induced reduction in urinary pH favors the crystallization of uric acid and further enhances the risk of urate stone (32). Renal colic is thus more common during warmer months (33). Additionally, studies suggest that males are more susceptible to developing kidney stones due to increased temperature. However, whether this is related to the total cumulative heat exposure or differential pathophysiological response is unclear (34, 35).

METABOLIC SYNDROME AND NEPHROLITHIASIS

The prevalence of metabolic syndrome in topical countries is on the rise (36-38). The upsurge in the frequency of nephrolithiasis could be attributed somewhat to the increasing burden of metabolic disorders. A consistent association between the prevalence of metabolic syndrome and renal stones has been demonstrated (39). Obesity, diabetes, hypertension, and insulin resistance, all components of metabolic syndrome, are risk factors for stone formation (40). Hyperuricemia, another manifestation of insulin resistance, is a recognized pathophysiologic link. Insulin resistance decreases urinary ammonium production leading to the formation of acidic urine, augmenting the potential for lithogenesis (41, 42). However, the predominant stone type in metabolic syndrome is oxalate. Hyperoxaluria in metabolic syndrome is multifactorial in etiology and could be related to changes in gut flora, increased renal oxidative stress, and alteration in the balance between promoters and inhibitors of lithogenesis (43, 44).

CHILDHOOD ENDEMIC BLADDER STONES

The incidence of vesical calculus has declined significantly over the last few decades in developed nations but is still prevalent in the tropics. Reliance on carbohydrate-rich food and lack of protein early in life results in a relative deficiency of phosphates and leads to the formation of insoluble urinary salts. The boys are predisposed as their long tortuous urethra is a hindrance to clearing the debris (45, 46).

OTHER VARIETIES OF RENAL STONE SPECIFIC TO TROPICS       

In a study from Taiwan, environmental melamine exposure was found to be associated with nephrolithiasis (47). Betel nut chewing is also linked to stone formation. The pathogenesis could be mediated by arecoline, an alkaloid in betel nut (48).

DENTAL DISORDERS IN THE TROPICS

Tropical oral disorders include a wide range of conditions that may be manifestations of systemic diseases. Osteoporosis continues to be one of the most underdiagnosed and under-reported conditions in the tropics. Though the diagnosis of osteoporosis is based on DXA, it has been suggested that signs in the oral cavity and dental X-rays can be used for primary screening in resource-limited settings. Several radiographic indices, such as mandibular cortical index, mandibular cortical width, antegonial Index, gonial index, panoramic mandibular index, and alveolar crest resorption degree (M/M ratio), have been explored as screening tools for osteoporosis (49).

The oral cavity can be a window to many other MBDs in the tropics. Vitamin D is crucial for the mineralization of bones and teeth. Low vitamin D levels lead to malformed, hypomineralized teeth that are brittle and vulnerable to decay, also known as “rachitic teeth (50). Dental abscesses are characteristic of vitamin D-resistant rickets (VDRR). Other characteristic manifestations of VDRR include dentin defects, unusually large pulp chambers, enlarged pulp horns, and enamel hypoplasia (51). Brown tumor, loss of bone density, soft tissue calcification, and dental abnormalities, such as developmental defects and changes in tooth eruption, are common oral symptoms in hyperparathyroidism. Malocclusion due to the drifting of teeth and spacing of the teeth may be the first signs of hyperparathyroidism (52).

Tropical infective diseases such as tuberculosis can atypically present with oral manifestations. Lesions in the jaw in the form of osteomyelitis or simple bone radiolucency, as well as superficial ulcers, patches, and indurated soft tissue lesions, are described (53). Dental fluorosis is caused by excessive fluoride ingestion during tooth development. Dental fluorosis is common in the tropics and is described in the previous section (54, 55). Clinically, mild cases of dental fluorosis manifest as an opaque white appearance of the enamel from increased subsurface porosity. Moderate dental fluorosis manifests as yellow to light brown staining in the areas of enamel damage. Severe dental fluorosis results in a porous enamel that is poorly mineralized and stains brown (56). Preventive strategies involve control of fluoride levels in drinking water (57).

SARCOPENIA AND BONE – A TROPICAL PERSPECTIVE

Sarcopenia, defined as the loss of muscle mass and strength, is an emerging global health problem. In a recent meta-analysis on the worldwide prevalence of sarcopenia, using different classifications and cut-off points, the prevalence of sarcopenia varied between 10 to 27% (58). Multi-center research from nine nations (Finland, Poland, Spain, China, Ghana, India, Mexico, Russia, and South Africa) across three continents revealed an overall frequency of 15.2% (59).

Types Of Sarcopenia

When no other etiology other than aging is apparent, the condition is called "primary" (or age-related) sarcopenia.  The term "secondary" sarcopenia refers to sarcopenia from one more additional cause (60). Many tropical countries are seeing a rapid increase in the aging population owing to improved healthcare facilities (61, 62). Hence, primary sarcopenia can potentially become a serious health concern globally, particularly in the developing world. Secondary sarcopenia could be activity related (resulting from bed rest, a sedentary lifestyle), disease-related (associated with endocrine diseases, advanced organ failure, malignancy, inflammatory disease), or nutrition-related (inadequate dietary intake of energy/protein, malabsorption, use of medications that cause anorexia, etc.) (60).

Risk Factors For Sarcopenia In The Tropics

Though the tropics have been plagued with communicable diseases for a long time, there is a recent increase in noncommunicable lifestyle diseases and obesity, major risk factors for sarcopenia (63, 64). A significant subset of adults over 65 years have sarcopenia complicated by obesity and are at risk of synergistic complications from obesity and sarcopenia (65). "Thin-fat obesity" or "sarcopenic obesity," also known as normal-weight obesity, is a recognized phenotype in South Asia with a comparable risk for cardiometabolic disease to conventional obesity. It is described as a condition in which a person has a normal body mass index (BMI) but a higher body fat percentage (based on ethnicity and gender-specific cut-offs) (66).

Muscle mass and strength are lower in South Asians than in Caucasians (67). The South Asian Working Action Group on Sarcopenia (SWAG-SARCO) consensus has been developed for diagnosing sarcopenia in South Asian nations while considering these ethnic characteristics (64). Malnutrition is still a significant public health issue in underdeveloped nations, notwithstanding the rise in obesity (68-70). In addition to the traditional risk factors, HIV-associated sarcopenia is prevalent in Africa. In a study from Brazil, HIV-infected patients had a 4.95 higher risk for sarcopenia than the controls, which persisted even following adjustments for age and BMI (71).

Osteosarcopenia

Numerous studies support the concept of a bone-muscle unit, in which molecules released by the skeletal muscle secretome influence bone, and the osteokines secreted by osteoblasts and osteocytes modulate the muscle cells (72). Duque et al. originally used the term "osteosarcopenia" to refer to an older population subgroup having both sarcopenia and osteoporosis. Clinically, unfavorable outcomes such as falls, fractures, loss of function, and frailty arise when both illnesses coexist. Resistance training, adequate protein and calcium consumption, and maintenance of optimum levels of vitamin D are simple therapies that have a dual favorable effect on bone and muscle and decrease falls, fractures, and disability (73).

CHALLENGES IN THE DIAGNOSIS AND MANAGEMENT OF MBD IN THE TROPICS

Prevalence Of Vitamin D Deficiency

Since skin exposure to ultraviolet radiation is the major source of vitamin D, it has long been believed that residing in tropical countries ensures adequate vitamin D levels. However, there is overwhelming evidence for widespread vitamin D deficiency in the tropics. Several other factors which could affect vitamin D levels, such as adiposity, skin pigmentation, genetic factors, clothing habits, sun avoidance, regular use of sunscreen, cloud cover and pollution, have been implicated (74).

Most studies have defined vitamin D insufficiency as serum 25(OH)D less than 50 nmol/L (20 ng/mL). Using this diagnostic cut-off, South Asia has a prevalence of vitamin D insufficiency of 70% or more, and the prevalence in Southeast Asia ranges from 6-70% (75).

Diagnosis Of Osteoporosis: Pitfalls And Challenges

The diagnosis and management of MBD in the tropics is fraught with challenges. The gold standard tool for measuring BMD is the dual-energy X-ray absorptiometry (DXA) scan (76). However, the limited availability of DXA and the associated costs continue to be  a major hurdle (77). The World Health Organization (WHO) defined T-score of ≤-2.5 SD, originally designed as an epidemiological tool, has been widely adopted as both a diagnostic and intervention threshold for osteoporosis (78). The (National Health and Nutrition Examination (NHANES III) Survey was employed to create the Caucasian reference database. NHANES III is a nationally representative sample of 14,646 women and men in the United States. The data from this survey is used as the reference database in most DXA machines (79, 80). There is a need to have country-specific reference ranges appropriate for the representative population (81, 82).

Utility Of Cost-Effective Screening Tools

To circumvent the challenges associated with the cost and availability of DXA machines, a number of cost-effective screening tools for osteoporosis have been explored. FRAX®, developed by the former WHO Collaborating Centre at the University of Sheffield, is the most widely validated and used fracture risk assessment tool (83). The risk of hip fracture and other osteoporotic fractures varies greatly globally. The FRAX models are calibrated to countries where fracture and death epidemiology is known to adjust for these fluctuations (84). Currently, FRAX is available in 65 countries, including two Asian, 35 European, nine Middle East and African, two North American, seven Latin American, and two Oceanian. However, country-specific FRAX thresholds are unavailable in many tropical countries (85, 86). Another screening tool of note, the Osteoporosis Self-Assessment Tool for Asians (OSTA),  has been validated in multiethnic population in Asian countries (87,88).These screening tools identify patients at high risk for osteoporosis and optimize use of DXA in resource-limited settings (89).

Osteoporosis Awareness

Studies in multiethnic populations across Asia have consistently demonstrated poor knowledge of osteoporosis among women (90-92). Similarly, poor awareness among at-risk populations is a major concern across regions of Africa and South America (93-95). Low awareness among physicians and healthcare authorities contributes to the enormous treatment gap in osteoporosis (93,96-98). Though osteoporosis and osteoporosis-related fractures have consumed significant health resources, it is not recognized as a health priority in tropical countries due to the ‘more’ essential diseases such as tuberculosis, malaria, and human immunodeficiency virus (94). Supporting research, raising awareness and establishing public health services will go a long way in preventing the enormous morbidity and mortality associated with fractures in these regions.

Fracture Liaison Services

FLS are gaining importance to address the low rates of patient work-up and treatment following a fracture. The FLS model attempts to avoid future fractures because there is at least a two-fold risk of refracture (99). The International Osteoporosis Foundation recommends the establishment of FLS to identify and treat patients with fractures properly. Universal FLS implementation in Brazil, Mexico, Colombia, and Argentina was predicted to prevent 31,400 fractures, avoid 292,281 bed days, and save 58.4 million USD in 2019 (100). However, FLS programs are yet to be universally established (100-102). Educating and engaging both private and public sectors in the efficient delivery of FLS could be a pragmatic solution to prevent osteoporotic fractures.

CONCLUSION

MBD is widely prevalent but often ignored in the tropics. Understanding the spectrum of MBD in the tropics will not only address the gap but may also throw light on unique pathophysiological aspects of bone metabolism. Nutrition, environment, infections, and genetic traits are responsible for the development of a diverse array of MBD in the tropics. Optimum utilization of resources is a key to tackle this challenge.

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ABSTRACT

The adrenal gland is essential for survival and its function is compartmentalized into specific zones. Disorders of the adrenal gland can be classified as those affecting the adrenal cortex or medulla. Pediatric adrenal disorders can have distinct presentations and etiologies in comparison to adults, such as adrenal insufficiency associated with genetic syndromes or Cushing’s syndrome associated with adrenocortical tumors and primary pigmented nodular adrenocortical disease. Congenital adrenal hyperplasia (CAH) has been commonly reported from the tropics, and rare variants of CAH have also been recognized in populations where consanguinity is prevalent. Pheochromocytomas and paragangliomas (PPGL) have been reported from tropical countries, some with rare presentations. The frequent rate of heritability and mutations in PPGL highlights the importance of genetic studies among children. The role of functional imaging is evolving for PPGLs as data is emerging from cohort studies. Disorders of Sex Development (DSD) comprise a heterogeneous group of disorders that can present in any age group. DSDs in childhood usually present with ambiguous genitalia and a multidisciplinary approach is required for its management. The diagnosis of adrenal disorders can sometimes pose a challenge in tropical countries due to resource constraints, lack of awareness, and access to medical care. However, available data from cohort studies and case reports have highlighted differences in etiology and presentation as compared to other parts of the world and the need for further studies.

INTRODUCTION

Adrenal disorders commonly seen in the tropics include adrenal insufficiency, congenital adrenal hyperplasia, adrenal Cushing’s syndrome, and pheochromocytoma/paragangliomas

Adrenal Insufficiency

It is characterized by decreased production of cortisol by the adrenals. The identification of adrenal insufficiency in children requires a high index of suspicion. This is important not only to prevent an adrenal crisis but to identify the associated comorbidities.  Acute adrenal crisis can present in infancy as a salt-wasting crisis or precipitated in children due to stressors such as illness, trauma, or surgery. They often present as an emergency with abdominal pain, vomiting, hypotension, hypoglycemia with seizures, and hyponatremia which eventually leads to shock and cardiovascular collapse if undiagnosed. Chronic adrenal insufficiency presents as prolonged neonatal jaundice, failure to thrive, hyperpigmentation, anorexia, fatigue, nausea and vomiting, salt craving, diarrhea, abdominal pain, postural hypotension, and tachycardia. A study from Pakistan characterized the presentation of children with adrenal insufficiency of which 19% presented with an adrenal crisis following an acute illness (1). The chronic symptoms reported were not different from that seen in another cohort form South Africa (2). Rare primary presentations of adrenal insufficiency as infantile cholestasis (3) and gigantism with motor delay have been reported (4).

The causes of adrenal insufficiency in children are different as compared to adults.  Etiologically it can be divided into primary and secondary adrenal insufficiency. It can also be seen as an isolated condition or in association with specific syndromes.

Primary adrenal insufficiency may be related to an underlying genetic or metabolic cause. Congenital Adrenal Hyperplasia (CAH) is the most common cause of primary adrenal insufficiency. Autoimmunity, infections, and hemorrhage are also important causes of primary adrenal insufficiency. The largest cohort study from Sudan diagnosed 80 children with adrenal insufficiency. The etiology ranged from Allgrove syndrome (36%), auto-immune polyendocrinopathy syndrome (11%), adrenoleukodystrophy (9 %), bilateral hemorrhage (1%), to unspecified (42%) (5). Case reports and series also reported similar causes such as Allgrove syndrome (6-8), adrenoleukodystrophy (9), to rare causes such as familial primary glucocorticoid deficiency (3), Steroidogenic acute regulatory protein (StAR) deficiency (10), Nuclear receptor subfamily 0, group B, member 1 (NR0B1) gene or DAX1 gene mutation (11) as well as primary multidrug-resistant adrenal tuberculosis (12).

The diagnosis of adrenal insufficiency is made by a peak cortisol value less than 18 mcg/dl on ACTH (Synacthen) stimulation test. A raised plasma ACTH level confirms primary adrenal insufficiency. The dose of Synacthen recommended for children less than 2 years is 15 µg/kg body weight and for children more than 2 years 250 µg im. However, Synacthen is not easily available in many countries. Acton Prolongatum, a long-acting synthetic ACTH preparation of the 39-amino acid native porcine sequence in a carboxymethylcellulose base has been studied and validated in India for the diagnosis of adrenal insufficiency in children > 5 years (13).

 NB: * Test is validated for children above 5 years (13). ** Studies in adults have also been done with 30 IU of Acton Prolongatum (0.5 ml) (95) (96).

Congenital Adrenal Hyperplasia

CAH is a group of autosomal recessive disorders characterized by enzymatic defects in adrenal steroidogenesis and diminished cortisol synthesis. The accumulation of precursors proximal to the blocked pathway and hypocortisolemia are responsible for the clinical features of these disorders. The presentation is varied and includes early classic presentation of salt-wasting (SW) and simple virilizing (SV) disorder to the non-classical presentation. Rare presentations of CAH as adrenal insufficiency (14), genital ambiguity (15) (16), hypoglycemia (17, 18), and precocious puberty (19) due to enzyme defects other than 21 hydroxylase deficiency have also been reported.

Newborn screen (NBS) for CAH from India revealed a prevalence of 1 in 576 (20). However retrospective data in the absence of NBS revealed the presentation of adrenal crisis in >80% of subjects with 70% presenting as SW-CAH and a delayed diagnosis in boys as compared to girls highlighting the importance of NBS (21).

CAH due to 21 hydroxylase deficiency (21OHD) accounts for 90-95% of the cases followed by 11β-hydroxylase deficiency (11βOHD), and 3β-hydroxysteroid dehydrogenase 2 (3βHSD2). Regional differences in the prevalence of enzyme deficiencies confirmed by genetic tests have been described from Cameroon (n=24) which found that 11βOHD was more common (66.6%) followed by 21OHD and as well from Algeria (n=273) which showed that 3βHSD2 (5%) was the second most common form after 21OHD. These differences may be attributed to the founder mutations (22, 23).

Diagnosis is made by screening for 17 OH Progesterone (OHP) which is elevated, followed by 17 OHP and other steroid responses to synacthen test. However, confirmation of specific enzyme deficiency requires genetic testing. The spectrum of genetic mutations has been described in various cohorts for CYP21A2, which was able to diagnose mutations in 80-96% of the subjects, and genotype-phenotype correlations have been established for various forms of CAH (24-27). Additionally, allele-specific PCR for screening common CYP21A2 mutations has been suggested as a cost-effective tool, especially in resource-constraint settings (28). The diagnosis of other enzyme deficiencies is often challenging due to a lack of genetic tests and steroid precursor assays. However, studies are emerging for other CAH variants such as 11βOHD from India (29) and 3β-hydroxysteroid dehydrogenase 2 (3βHSD2) deficiency from Algeria (23) with the discovery of novel mutations indicating genetic heterogeneity. Combined genetic mutations have also been reported (30).

A child diagnosed with CAH requires lifelong treatment and monitoring. A longitudinal data from Egypt indicated that CAH subjects with older age, poor hormonal control, and frequent hospitalizations have relatively poorer health-related quality of life. The challenges faced in the management of CAH include late diagnosis, poor follow-up (31), and the development of adrenal rest tumors (23, 29).

Cushing Syndrome

Cushing syndrome is suspected in a child who presents with weight gain and growth failure. The characteristic cushingoid features described in adults are usually not seen and they often present with generalized obesity. Endogenous Cushing syndrome varies with the age of diagnosis with adrenal tumors predominating in children < 7 years and Cushing disease after 7 years. However, it is important to note that the most common cause of Cushing’s syndrome is exogenous and even topical routes of administration have been implicated in children (32-34).

Of the ACTH-independent Cushing syndrome, primary pigmented nodular adrenocortical disease (PPNAD) has been the most frequently described from the tropics in case series and reports some of which have been found in association with Carney’s complex (35-39). The other important cause reported is in association with Adrenocortical tumors as described below.

Adrenocortical Tumors

These tumors account for 0.2% of all pediatric tumors. The largest case series from India with 17 cases reported that 82% presented with endocrine dysfunction, of which the most common was Cushing syndrome with or without virilization seen in 53% of the subjects (40). Another cohort of 7 children from Sri Lanka also reported peripheral precocious puberty in all the subjects and one boy had the phenotypic features of Beckwith–Wiedemann syndrome (41). Case reports have also reported similar presentations some of which are the rare variants of adrenocortical oncocytoma (42-49). Large non-functioning adrenal cortical carcinoma can present with mass effects without any features (40, 50). The prognosis depends on the diagnosis with adenomas having complete remission. However, the prognosis of subjects with carcinoma was poor (40) (41).

Pheochromocytomas and Paragangliomas

Pheochromocytoma (PCC) refers to the catecholamine-producing tumor of the adrenal medulla whereas paragangliomas (PGL) are extra-adrenal tumors of sympathetic and parasympathetic ganglia. Of the PPGLs, 10-20% occur in the pediatric age group. There is a high rate of germline mutations and heritability in pediatric PPGLs. A cohort of 30 children from India with PPGL showed that 26.7% of the subjects had syndromic or familial association, of which Von Hippel-Lindau was the most common. Fourteen (46.7%) children had germline mutations (VHL 10 (33.3%), SDHB 2 (6.6%), and SDHD 2 (6.6%). Bilateral pheochromocytomas and symptomatic presentation was more frequent in children as compared to adult PPGL. Children with VHL mutation had more frequent bilateral PCC, coexisting PGL and recurrence (51).

PPGLs often mimic other diseases and rare presentations such as myocarditis (52), diabetes insipidus (53), hypertensive encephalopathy (54) (55), Cushing syndrome (56), pseudo renal artery stenosis (57), and papilledema (58) have been described.  

After biochemical confirmation, imaging studies are advised for anatomical localization. Functional imaging is recommended for larger tumors, suspected multifocal or extra adrenal tumors, succinate dehydrogenase subunit B (SDHB) or alpha-thalassemia/mental retardation syndrome X-linked mutations (ATRX) and dopamine secreting PPGLs. A cohort study from India revealed that 68Ga-DOTATATE PET/CT (95%) had a higher sensitivity than 18F-FDG-PET/CT (80%) and 131I-MIBG (65%) for overall lesions. 68Ga-DOTATATE PET/CT was more sensitive than 131I-MIBG (93 vs. 42%) for detecting metastases (59).  The definitive management of PPGL is surgical resection. Pre-operative preparation with experienced anesthetic (60) and surgical team (61) is important for successful outcomes following surgery. The management of metastatic PPGL is challenging especially in countries with limited resources. Fractionated low dose 131 I-metaiodobenzylguanidine (MIBG) therapy has been used in the treatment of metastatic paraganglioma (62). Lifelong surveillance is recommended in children to detect early recurrence (63).

DISORDERS OF SEX DEVELOPMENT (DSD)

DSD is a condition in which chromosomal, gonadal, or anatomical sex is atypical (64). Observational studies from Egypt and Cameroon reported that these constitute 2-9.4% of the subjects presenting to endocrine clinics (65, 66).

Epidemiology

DSDs can be broadly classified into sex chromosomes, 46 XX and 46 XY DSDs. Cohort studies have revealed a prevalence of 5-15 % for sex chromosomal DSDs, 33.7-71% for 46 XY DSD, and 24-51% for 46 XX DSD (65-67). Regional differences were observed in the prevalence of these disorders attributed to consanguinity and endogamous marriages (66).

Clinical Features

DSDs have a varied presentation which includes ambiguous genitalia of varying severity, primary amenorrhea, and virilization at puberty to infertility in adulthood. The recognition of DSDs has critical implications due to their syndromic associations such as Wilm’s tumor and renal failure with Denys-Drash syndrome, adrenal insufficiency with CAH, and future risk of gonadoblastoma. In addition, there are long-term social and psychological impacts such as gender of rearing and fertility prospects. 

46 XY DSD

46 XY DSD can be classified as disorders of testis development, androgen synthesis, or androgen action.

The most common DSD reported among these are disorders of androgen synthesis of which 5 alpha reductase deficiency is the most commonly reported with a prevalence of 10%- 33% with a presentation as ambiguous genitalia (65-68). The higher rates reported in recent literature are attributed to the genetic confirmation some of which are novel and founder mutations, as opposed to the earlier diagnosis based on biochemical ratios of Testosterone: Dihydrotestosterone (69-71). Rare variants of CAH with presentation as infertility, hypertension, or virilization been reported (15, 72-74).

Androgen insensitivity syndrome (AIS); partial (PAIS) or complete (CAIS) is the next most commonly reported 46 XY DSD from various countries with a prevalence of 5-28% (65-67, 75, 76). However, cohort studies with genetic confirmation reported a prevalence of 10-38% (77, 78). A point to be noted was that only 31% of patients with a provisional diagnosis of PAIS had pathogenic variants in the AR gene (78). Patients with CAIS are reared as females and have a later presentation with primary amenorrhea. The presentation of PAIS may be earlier with atypical genitalia or gynecomastia.

The third most commonly reported cause is gonadal dysgenesis which can be partial or complete with a prevalence of 4-10% (65-67, 79), Case reports of gonadal development disorders with dysgenesis are also emerging which include WT-1 mutation (80-82), Desert hedgehog (DHH) gene (83), and Mitogen‐activated protein 3 kinase 1 (MAP3K1) gene (84). 

Other rare causes such as persistent Mullerian duct syndrome (85, 86) and Leydig cell hypoplasia (87) have been reported from the Middle-eastern countries.

Syndromic causes of 46 XY DSD accounts for 1-1.8% of the cohort studies cited earlier.

46 XX DSD

In contrast to the 46 XY DSDs which can have variable presentation and etiology, the most common cause of 46 XX DSD is CAH of which 21 hydroxylase deficiency is the most common cause. However, Sap et al from Cameroon reported 11 hydroxylase was the most common cause of CAH in their population (66). The prevalence of 46 XX DSD ranges from 20%-55% (65-67). 

The other important causes of 46 XX DSD are ovotesticular DSD (16.2%) and vaginal atresia (2%). Rare case reports of aromatase deficiency (88) and isodicentric Y chromosome in 45 X individuals have been reported (89). 

Management

The diagnosis and management of DSDs are challenging, especially in countries with low resources. The most important step in the initial evaluation of ambiguous genitalia is the presence of gonads which gives us a clue in narrowing the cause and guiding further workup. Karyotyping, imaging by pelvic USG or MRI, followed by biochemical evaluation helps in establishing a diagnosis. The emergence of genetic tests has further simplified the evaluation of such patients and will prove to be a valuable tool in the future.

Diagnosis of DSD and gender assignment has lifelong implications for the patients. There have been reports of gender change and gender identity confusion especially in 46 XY DSDs (90-92). However, patients with AIS have less prevalence of gender dysphoria (77, 92).

For 46 XX DSDs with virilization, feminizing genitoplasty is an important concern especially the timing of surgery. An observational study from Malaysia of 59 females with CAH who had undergone feminizing genitoplasty (FG) reported that infancy and early childhood as the best timing for first FG, most preferring single-stage over 2-stage surgery (93).

Data regarding the risk of gonadoblastoma and prophylactic gonadectomy is scarce. A case series of 5 subjects of 46 XY DSD reared as females revealed malignancy in only one patient with CAIS (94).

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ABSTRACT

Pediatric endocrine disorders are frequently seen in tropical countries. While broadly the spectrum of pediatric endocrine disorders in the tropics is not entirely different from that seen in other parts of the world, some aspects of these disorders are unique to the tropics. Many pediatric endocrine disorders are underreported from the tropics, presumably because of limited access to medical care in terms of both diagnostic and therapeutic facilities. Lack of formal training of pediatricians and physicians in pediatric endocrinology may be a contributor. Some conditions such as exogenous Cushing syndrome are seen very frequently in tropics because of easy access and unrestrained use of glucocorticoids by quacks/ faith healers. Malnutrition is an important contributor to short stature in many tropical countries where a large section of the population is living in abject poverty. Iodine deficiency disorders are seen in many countries despite iodine fortification of salt or other edible items. Lack of universal screening for congenital hypothyroidism often leads to late detection of this disorders contributing to significant morbidity and mortality. Vitamin D deficiency and nutritional rickets is rampant even in areas where sunlight is abundant year around. Since most of the pediatric endocrine disorders are easily treatable and can have severe consequences when diagnosis or treatment is delayed, increasing the awareness of these disorders in the healthcare workers in the tropics is necessary.

PITUITARY DISEASE

The common pituitary disorders reported from the tropics include craniopharyngiomas, growth hormone deficiency, pituitary adenomas (including prolactinomas), and Cushing’s disease.

Craniopharyngiomas

Craniopharyngiomas are common suprasellar tumors in childhood.  A retrospective analysis of 62 pediatric (onset <18 years) craniopharyngiomas was reported from a tertiary care hospital from India. The presenting features included central diabetes insipidus (6.5%), central hypothyroidism (43.5%), secondary adrenal insufficiency (32%), and delayed puberty (24%). On follow up 90% had some form of anterior pituitary deficiency and 22.6% developed obesity. GH therapy was given to 14% of cases.  Incomplete  surgical removal was frequent and radiotherapy was used in many cases (1). Another study from Egypt reported 137 patients with pediatric craniopharyngiomas. They were treated with surgery alone (65), radiotherapy after surgery (71), or surgery for Ommaya insertion with intracystic interferon injection (1). Subtotal resection was seen in 58 patients (42.33%) while 48 cases (35.04%) had gross total resection/near total resection. The  5-year progression-free survival (PFS) was 52.3%, ( surgery alone 34.49% and  radiotherapy after surgery  72.25% ) (2). Both craniopharyngiomas and gliomas were most common supratentorial pediatric brain tumors in Nigeria (3). In a study of 37 pediatric craniopharyngiomas who underwent surgery, gross total resection was possible in 43.2%, near total resection in six patients 16.2%.  and subtotal resection (STR) in 40.5%. The recurrence-free survival rate was 81.1% and 70.3% at 5- and 10-year follow-up, respectively. Diabetes insipidus, anterior pituitary hormone deficits, and obesity were common in follow up (4). In a study from Pakistan, craniopharyngiomas were 14.3% of the reported pediatric intracranial tumors (5). Another study from Pakistan has reported the use of gamma knife radiosurgery in craniopharyngiomas. The patients included 17 children. Nearly 80% of the patients achieved tumor control with gamma knife (6). An uncommon variant called papillary craniopharyngiomas  has been reported in 13 cases from Pakistan (7).

Growth Hormone Deficiency And Related Disorders

Isolated growth hormone deficiency (IGHD) and combined pituitary hormone deficiency (CPHD) are the two presentations of growth hormone (GH) deficiency. The mutations involved in IGHD are GH1 and GHRHR while CPHD is associated with mutations in transcription factor genes PROP1, POU1F1, and HESX1. Genetic analysis performed in 51 patients with CPHD at a tertiary care center in India reported that 10 (20%) patients had POU1F1 and PROP1 mutations and of these 5 were novel and 2 previously reported. No mutations were identified in HESX1 (8).

A study of growth hormone deficient patients from South India reported that smaller pituitary size was associated with worse height deficits and bone age delays. However, they had a  better response to GH therapy (9).

Children with IGHD had several biochemical and cardiac parameters that may be associated with an increased CVD risk in later life. This included higher waist-hip-ratio, total cholesterol, non-high-density lipoprotein-cholesterol, serum homocysteine, C-reactive protein (CRP), and pro-brain natriuretic peptide (pro-BNP). Left ventricular mass (LVM) and interventricular septal thickness were significantly lower (10).

A novel POU1F1 c.605delC mutation in combined pituitary hormone deficiency (CPHD) was identified by Sanger sequencing carried out in 160 trios and 100 controls. In vitro studies showed that the this mutation codes for a truncated protein with reduced transactivation capacity on downstream targets like  growth hormone (GH) and prolactin (PRL) (11).

Laron dwarfism first reported among Israeli Jewish children is a rare disorder characterized by low IGF-1 and high GH levels. A case series of nine such cases (6 male, 3 female) was reported from South India. The short stature was extreme with a mean height Z score of 7.7 (SD 0.8).  Clinical features included characteristic facial features, microcephaly, micropenis and developmental delay. All children had typical hormonal profile of low IGF-1 and elevated GH (12). Laron syndrome has been reported from Africa and South America (13)(14)(15).

Pituitary Adenomas

While adult pituitary tumors are relatively common, pediatric pituitary adenomas (PPA) are less common. A retrospective study of 74 cases of PPA was published from a center in North India. The median age was 15 years and 42 % were females. Headache and menstrual abnormalities were common presentations. Corticotroph adenomas (32.4%) and somatotropinomas (25.7%) were among the common types. TSHoma and pituitary blastomas were very few. In 81% cases, transsphenoidal surgery was performed while adjuvant medical management and radiotherapy was required in 25% and 18% respectively. Remission rates in Cushing's and acromegaly were 62.5% and 57.8%, respectively, and post operative hormone deficits were seen in 33% (16).

Giant prolactinoma (GP) are rare pituitary tumors in childhood and adolescence. A series of 18 cases of GP has been reported from India. GP constituted 20% of pediatric prolactinomas at this center. The authors conducted a systematic review including these 18 and 77 other cases from the literature. They found a male predominance with pubertal arrest/delay. Dopamine agonist (DA)  monotherapy showed good results as monotherapy (17).

Cushing’s Disease

Cushing’s disease is an important cause of hypercortisolism in children. It is caused by an ACTH secreting pituitary adenoma. A retrospective study of 48 pediatric cases of Cushing’s disease who underwent transsphenoidal adenectomy between 1998 and 2008 was published from India. Weight gain, round facies, and short stature were the most common clinical manifestations. Low dose dexamethasone suppression test and midnight cortisol showed 100% sensitivity for establishing hypercortisolism, while midnight ACTH had 100% sensitivity for confirming ACTH dependence. Magnetic resonance imaging and unstimulated BIPSS were used to confirm Cushing’s disease. Post surgical remission was 56% after first transsphenoidal adenectomy with higher remission rate of 75% in those with microadenoma. Eight patients were given radiotherapy and four of these achieved remission (18).

GROWTH AND PUBERTAL DISORDERS

Short stature and delayed puberty are commonly seen in children visiting pediatric endocrine clinics in the tropics.

Short Stature

Malnutrition, systemic illnesses, endocrine disorders, and syndromic disorders are among the major causes of short stature in the tropics.

MALNUTRITION

Malnutrition in early childhood is an important cause of short stature in tropical counties. The role of early childhood undernutrition on physical growth and cognitive achievement was assessed in a nationwide population-based cohort study in India. Data on undernutrition was taken from Human Development Survey (IHDS) in 2004 to 2005 while the outcomes on physical and cognitive outcomes during preadolescent (8 to 11 years) years was assessed in 2011 to 2012. The study assessed 7868 children and 4334 were undernourished. Undernourished children had 1.73 times increased odds of short stature. It was associated with decreased odds of achieving a higher reading and arithmetic outcomes. The findings were worse in female children.(19)

SYNDROMIC SHORT STATURE AND OTHER CAUSES

Noonan syndrome (NS), an autosomal dominant disorder, is caused by mutations in genes associated with the RAS / mitogen-activated protein kinase (MAPK) pathway. A large series of 363 patients with Noonan’ syndrome was published from India. The exons of PTPN11 gene were sequenced in all patients. Congenital cardiac anomalies (mostly right sided defects) were present in 84% of patients. The downward-slanting palpebral fissures, hypertelorism, low-set posteriorly rotated ears, short stature, pectus excavatum, and unilateral or bilateral cryptorchidism were common clinical findings. The most common variants in this series were in exon 8 (c.922A > G, c.923A > G), observed in 22 of the affected. Thirty-two previously described pathogenic variants in eight different exons in PTPN11 gene were detected in 107 patients (20). Similar findings were reported from a study in Morocco (21). Noonan syndrome has been described in Latin America, Africa and other countries in Asia. The facial characteristics of Noonan syndrome cases worldwide  were similar to those of European descent (22).

Achondroplasia is a skeletal dysplasia that is a common cause of disproportionate short stature. In a study of forty cases with disproportionate short stature from India , achondroplasia was the most common skeletal dysplasia with  c. 1138 G>A, p. Gly380Arg mutation seen in all cases (23). Achondroplasia has been reported from Pakistan and Africa also (24,25).

Idiopathic short stature (ISS)refers to the short stature where all the conventional clinical and biochemical work up is normal. Genetic studies in 61 patients with ISS in India showed that four patients had a heterozygous variant in SHOX gene while two had novel, likely pathogenic variants, in the IGFALS gene (26).

Thalassemia is a frequent cause of short stature and pubertal delay. Inadequate chelation therapy and lack of awareness among treating physicians on endocrine complications lead to higher prevalence of undiagnosed endocrine issues in these children. In a study from central India, short stature (88%), delayed puberty (71.7%), hypothyroidism (16%), and diabetes mellitus (10%), were reported in children with thalassemia (88).

Puberty

Pubertal disorders can be broadly classified as delayed puberty and early (precocious puberty). Secular trends of gradual reduction in the age of puberty have started becoming apparent in tropics.

SECULAR TRENDS IN PUBERTY

The age of normal puberty has shown a decline in many tropical countries- a trend which mimics that witnessed in the developed world decades earlier. Data regarding normal puberty from Egypt suggests that in girls with BMI ≥85th percentile all pubertal stages started earlier as compare to girls with BMI less than 85^th centile. No such association between BMI and pubertal stage was noticed in males (27). A decline in the age of pubertal maturation of girls in Nigeria was also reported. The median age at beginning of breast maturation (B2) and menarche were 9 and 12 years respectively. The age at menarche was significantly associated with overweight/obesity and high social class (28). Similar findings have been reported from India where a study of 2010 school girls reported that median age of thelarche and menarche was 10.8 and 12.4 years with obese girls showing a six month earlier onset of thelarche and menarche when compared to those with normal BMI (29). Similar findings were reported from Western India (30). School girls in Riyadh, Saudi Arabia also had earlier onset of puberty similar to that seen developed countries (31).

DELAYED PUBERTY

Delayed puberty is a common pubertal disorder. It may be a normal variant such as constitutional delay in growth and puberty or represent a pathology. Pathological causes are classified as hypogonadotropic or hypergonadotropic hypogonadism. In a retrospective study of 136 patients with delayed puberty from Sudan, permanent or functional hypogonadotropic hypogonadism was seen in 37.5 and 36% while hypergonadotropic hypogonadism was seen in 11.7%. Constitutional delay in growth and puberty was present in 14.7%. Type 1 diabetes and celiac disease were common systemic illnesses (32). A study of 42 cases of delayed puberty from India (19 boys, 23 girls) underlying systemic illnesses were the dominant cause of pubertal delay in girls (11/23) while the major cause in boys were endocrinopathies (6/19). Malnutrition, chronic infections, and anemia were common systemic illnesses (33).

An unusual association of hypopituitarism along with Turner syndrome was reported in six Tunisian patients (34).  A study of 11 Turner syndrome patients was reported from Cameroon, seven had monosomy while four had mosaic Turner syndrome. Most of these had presented with delayed puberty or short stature. Other clinical features were short neck, forearm carrying-angle deformity, a low hairline, and a webbed neck. Horse shoe kidney was found in two cases but none had cardiac abnormalities. The average age at diagnosis was 18.4 years indicating a delay in the diagnosis (35).

Differentiation between CDGP and hypogonadotropic hypogonadism is challenging in tropical countries. Most patients do not have regular height measurements and estimation of growth velocity in the years preceding to the presentation is often not possible. GnRH stimulation test has been employed but has limited utility because of significant overlap in the hormonal levels between the two groups. GnRHa-stimulated inhibin B (GnRH-iB) has been developed as a convenient test to differentiate between CDGP and hypogonadotropic hypogonadism. A cut-off value of 113.5 pg/ml in boys and 72.6 pg/ml in girls could  predict  spontaneous pubertal onset with  100% sensitivity and specificity (36).

PRECOCIOUS PUBERTY

Precocious puberty is a common pubertal disorder. It is classified as central precocious puberty (caused by premature activation of the hypothalamic-pituitary-gonadal axis) or peripheral precocious puberty (due to secretion of gonadal steroids from other causes without activation of the hypothalamic-pituitary-gonadal axis).

A retrospective analysis of 55 children (36 girls) with precocious puberty was reported from India. Central precocious puberty occurred in 62% (34 cases, out of which 19 were idiopathic) while peripheral precocious puberty was found in 14 children. The  commonest cause of peripheral precocious puberty  was congenital adrenal hyperplasia (46%) (37). A rare case of precocious pseudopuberty due to a virilizing adrenocortical carcinoma progressing to central precocious puberty after surgery has also been reported (38). Idiopathic precocious puberty responds well to GnRH analogue therapy as reported from a series for India (39).

There appears to be an increase in the incidence of central precocious puberty especially in girls in the COVID-19 lockdown in India as compared to the pre-lockdown period (40).

DISORDERS OF BONE AND MINERAL METABOLISM

Vitamin D deficiency and nutritional rickets are very common in tropics.  Primary hyperparathyroidism and less common forms of rickets like vitamin D resistant and hypophosphatemic rickets also occur.

Vitamin D Deficiency And Nutritional Rickets

Tropical countries have high prevalence of nutritional rickets. The human body can generate vitamin D in the skin from sunlight. Although tropical countries get abundant sunlight, vitamin D deficiency (VDD) is common. Harsh summers limit sunlight exposure in many tropical countries. Adequate sunlight exposure was found in only 27 % neonates in Ethiopia (41). In some countries, atmospheric pollutions limits sunlight penetration in winters (42). Darker skin color with high melanin content, different socio-cultural factors, and genetic variation also contribute to vitamin D deficiency. Infants are at a high risk of vitamin D deficiency which could be due to low vitamin D content in breastmilk, and inadequate vitamin D content of complementary foods and maternal vitamin D deficiency. Routine vitamin D supplementation  at a dose of 400 IU per day till 12 months of age in breastfed infants has been recommended in India (43). Oral vitamin D  supplementation of mothers during lactation has been shown to reduce risk of vitamin D deficiency in infants at 6 months of age by almost 95% (44). Nationwide data from India suggests that prevalence of vitamin D deficiency defined as serum 25OHD <12 ng/ml was 14% (1-4 years), 18% (5- 9 years), and 24%  (10-19 years) (43). However, VDD  prevalence ranging from 60-87 % has been reported in low birth weight infants and 71-88% in normal birth weight infants in Delhi, India (45) (46). In Uganda, a study found that prevalence of VDD in LBW infants was 12.1 % but most of these had received supplemental vitamin D (47). A larger study including five countries from sub-Saharan Africa, showed that prevalence of vitamin D deficiency in children aged 0-8 years was 7.8% (48). Countries closed to the Equator had less VDD. In India, a study from the state of Kerala reported a VDD prevalence of 11.1%. The reasons implicated for this relatively lower prevalence were latitude and fish intake in the diet (49). Data suggests that in several African countries nutritional rickets is common although VDD prevalence is not high. Children requiring surgical correction of deformities resulting from rickets in Malawi, Africa had lower dietary calcium intake but VDD was uncommon (50). Low dietary calcium intake has been implicated as a causative factor for rickets in Studies from Nigeria and Bangladesh (51,52). Serum alkaline phosphatase has been explored as a low-cost biochemical test to screen for nutritional rickets in children in Nigeria. A cut off of ALP > 350 U/L has been proposed in one study (53).Severe vitamin D deficiency can present as osteomalacic myopathy in children and adolescents (54).

For the treatment of  rickets and vitamin D deficiency, oral cholecalciferol in a daily dosing schedule (2000 IU below 1 year of age and 3000 IU in older children) for 12 weeks has been recommended by some Indian guidelines (43). However, compliance issues are common in underprivileged populations. When compliance to daily dosing cannot be ensured, this guideline has suggested intermittent regimen provided the child is above 6 months of age. Sunlight exposure was shown to be inferior to oral vitamin supplementation (400IU/day) in preventing rickets or vitamin D deficiency in infants in India (55). A single intramuscular dose of 600,000 IU of vitamin D has shown to be safe and effective for treatment of nutritional rickets in India (56).

Primary Hyperparathyroidism

Pediatric primary hyperparathyroidism (PHPT)has been reported in two studies from India. George et al performed a retrospective analysis of 15 children and adolescents with PHPT (age <20 yr.) between 1993 and 2006. The mean age was 17.7 (range 13-20 years) with 80% of patients being female. Clinical features included bone pain, proximal myopathy, bony deformities, fractures, palpable osteitis fibrosa cystica, nephrolithiasis, and acute pancreatitis. No cases had evidence of multiple endocrine neoplasia. Nearly a third of the cases developed post-operative hungry bone syndrome occurred in 33.3%. Histology was suggestive of parathyroid adenoma in all cases (57). Sharanappa et al reported retrospective data (September 1989-August 2019) of 35 pediatric PHPT patients (< 18 years) who underwent parathyroidectomy. The mean age was 15.2±2.9 years and with male to female ratio of 1:1.9. Skeletal manifestations were seen in 83% while renal manifestations occurred in 29%. Parathyroid adenoma was present in 91.4% patients, whereas the remaining had hyperplasia. Except one patients all others had  hungry bone syndrome in postoperative period (58). Adolescent PHPT can present as posterior reversible encephalopathy syndrome (59). Neonatal severe hyperparathyroidism is a rare disorder. One such case has been reported from India (60).

Other Forms Of Rickets

A case series of 36 patients with refractory rickets published from India reports that renal tubular acidosis (63%), vitamin D dependent rickets (14 %) (VDDR I in 2 and VDDR II in 3 patients), chronic renal failure (11%), hypophosphatemic rickets  (6 %), and chronic liver disease (6%) were common causes (61). Pseudohypoparathyroidism may also present with bony deformities resembling rickets (62). Hereditary vitamin-D resistant rickets was reported in eight patients in Tunisia. Two mutations in vitamin D receptor gene were found: p.K45E (5 patients with alopecia) and a novel p.T415R mutation located in the ligand-binding domain.

X linked hypophosphatemic rickets is the most common cause of phosphopenic rickets. It can be caused by loss of function mutations in the PHEX gene which leads to an increase in the phosphaturic hormone fibroblast growth factor-23 (FGF-23). Two novel mutations in the PHEX gene has been reported from two families from India (63). A family suffering from XLH has been reported from Pakistan (64). Idiopathic tumoral calcinosis (ITC) refers to the deposition of calcium hydroxyapatite crystals or amorphous calcium usually in juxta-articular tissue in a tumor-like fashion. ITC has been reported in  an 8-year-old child who had the symptoms  at 4 years of age (65).

THYROID

Common thyroid disorders in pediatric age group include hypothyroidism, iodine deficiency disorders, thyroiditis, and thyroid cancer

Congenital Hypothyroidism

Congenital hypothyroidism can be a devastating disease if not diagnosed and treated on time. Congenital hypothyroidism is much more common in tropical countries as compared to developed world. The prevalence in India is estimated to be one in 1000-1500 births (66). The Indian Society for Pediatric and Adolescent Endocrinology (ISPAE) has published guidelines on  screening, diagnosis, and management of congenital hypothyroidism (66,67). High prevalence of CH has been reported from Sri Lanka as well as Iran (68,69).  A cut off of ≥20 mIU/L for capillary TSH screening for CH  beyond 24 hours of life has been proposed in the India for deciding on recalling the patient for further workup while a repeat capillary sample was advised for TSH values between 10 and 20  mIU/L (70).

Despite the above research, most tropical countries do not have universal screening for CH. This contributes to significant morbidity due to this potentially treatable condition.

Iodine Deficiency Disorder

Iodine deficiency disorders are among the top causes of thyroid disease worldwide. Several tropical countries are affected by IDD. India and Pakistan have both initiated fortification of common salt with iodine. This measure has been successful in reducing total goiter rate in children, indicating an improvement in iodine status. However, several underprivileged populations in both countries have evidence of iodine deficiency (71,72). Africa also had a high prevalence of mild to moderate iodine deficiency but several iodine fortification programs have been started which resulted in improvement in the overall iodine status. Some high risk populations such as pregnant females may still face iodine deficiency (73).

Thyroiditis

A case series of 97 children with Hashimoto’s thyroiditis aged 5-12 years has been reported from India. The children were followed up for a six-month period.  Goiter was seen in 89 while eight had an atrophic form. The mean age was 9.9 years and the male to female ratio was 1:5.4. Overt hypothyroidism was present in 73.4% while hyperthyroidism was seen in 3.1%.  13.2 % were subclinical hypothyroidism and 10.3% were euthyroid. A large percentage of subclinical hypothyroid and euthyroid children developed overt hypothyroidism in the 6 month follow up. (79)

It is possible that the prevalence of autoimmune thyroiditis has increased after iodine fortification of the diet. In a case control study, 43 children with goiter and autoimmune thyroiditis were compared with 43 children with euthyroid goiter without autoimmune thyroiditis. Urinary iodine concentration (UIC) was significantly higher in children with autoimmune thyroiditis. A positive correlation between UIC and antimicrosomal antibody titers was found. A UIC  ≥300 μg/L  was strongly associated with autoimmune thyroiditis (80).

Hypothyroidism

Acquired hypothyroidism in most tropical countries is now predominantly autoimmune, barring those where severe iodine deficiency is still prevalent.

The control of hypothyroidism with levothyroxine therapy in children in tropical countries is often poor because of poverty, lack of proper advice, and reduced access to laboratory testing. Research work on treatment of hypothyroidism is being done.  Both bedtime and early morning intake of thyroxine had equal efficacy in maintaining a normal TSH in children with hypothyroidism in a randomized controlled trial from North India (78).

Van Wyk Grumbach syndrome is a syndrome characterized by prolonged untreated hypothyroidism, short stature, and isosexual precocious puberty. This syndrome is considered to be rare with very few cases reported so far in recent times. However, many cases of Van Wyk Grumbach have been reported from tropical countries like India and Sri Lanka (74,75,76). A case series of this rare syndrome has been reported from Pakistan (77). This illustrates that availability of trained physicians as well as laboratory facilities is still a challenge in tropical countries.

Hyperthyroidism

Pediatric hyperthyroidism has been reported in the tropics. Graves’ disease is the most common cause of pediatric hyperthyroidism. The factors differentiating pediatric Graves from adult disease are predominance of neuropsychiatricsymptoms, gradual and often insidious onset, and absence of infiltrative ophthalmopathy.

In a seven-year period, 24 children with hyperthyroidism were reported in a study from India.  Twenty of these had Graves’ disease while one had toxic nodular goiter and one had neonatal Graves’ disease while the remaining two were factitious. Behavioral problems, excitability, hyperkinesis, and irritability were most common symptoms. Ocular involvement was present in 85% while 30 % had cardiac involvement. Goiter was noted in 18 out of 24 cases. Carbimazole was used for treatment and remission occurred in seventeen cases (81). Neonatal thyrotoxicosis has been reported from India (82).

A case of a three and a half-year-old boy who had an  autonomous functioning thyroid nodule which was cured by radioiodine ablation has been reported from India (83). Radioiodine therapy has been used for pediatric and adolescent Graves’ disease. Carbimazole therapy does not appear to influence the outcome of radioiodine therapy (84). Thyroid storm precipitated by empyema thoracis has been reported in a 16 year old girl (85).

Thyroid Cancer

Thyroid cancer is not common in pediatric populations and usually occurs as papillary carcinoma (PTC). A publication from a oncology center in India reports that pediatric differentiated thyroid cancer has high rates of extrathyroidal involvement as well as lymph node and distant metastasis (86). These findings however are not unique to tropical countries as similar profile has been reported from other parts of the world. Pediatric PTC often do not have TERT  promoter mutations and have a lower prevalence of BRAFV600E mutation as reported in a study from India (87). Globally, the mortality rates of pediatric PTC are similar to that of adult PTC. The data on survival in pediatric PTC from tropical countries is limited.

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