The clinical features associated with Donohue syndrome are mostly present since birth, although they may show considerable individual variation [1] [2].

Leprechaunism is clinically manifested by abnormal growth, dysmorphic facies along with abnormalities of the endocrine organs [3].

Growth delays are present in a majority of the infants affected, with low birth weight and a failure to thrive being amongst the common manifestations. These infants are often emaciated, with underdeveloped muscles and/or bones. Bone age and maturation are delayed as compared to their peers.

A characteristic craniofacial structure helps in identifying infants with leprechaunism. Affected infants may show a wide variety of distinctive facial features such as underdeveloped, huge, low-set ears; macrostomia with thickened lips; hypertelorism; microcephaly; and a flattened nose.

A vast majority of infants also present with certain dermatological features, with the skin being abnormally thickened (pachyderma) and pigmented (acanthosis nigricans). An absence of subcutaneous body fat, hirsutism, and dysplastic nails may also be seen.

Endocrine disturbances form the other crux of the clinical abnormalities seen in patients with Donohue syndrome. Hyperinsulinemia is a common finding in such infants, owing to the absence of functional insulin receptors due to homozygous/ heterozygous mutations in the INSR gene [4] [5] [6]. Postprandial hyperglycemia and fasting hypoglycemia are frequently observed. Affected females may have cystic ovaries and an abnormally enlarged clitoris/ breasts, while males may be afflicted with an abnormally large penis. Cardiac lesions such as hypertrophic cardiomyopathy may also be observed.

Other abnormalities that have been observed in infants with leprechaunism include recurrent infections, abnormalities of the intellect and unusually large hands and feet. Abdominal complaints such as a distended stomach, cholestasis, iron accumulation in the liver and umbilical/ inguinal hernia have also been seen in some patients.

Infants with Donohue syndrome are reliably diagnosed by identifying the characteristic clinical features, along with biochemical and genetic evaluations to confirm the same.

The biochemical abnormality most commonly observed in these infants is hyperinsulinemia, with levels commonly exceeding 1000 pmol/l. Some patients may show insulin levels > 50,000 pmol/l.

The diagnosis of leprechaunism is confirmed by the presence of mutations in the insulin receptor gene (INSR 19p13.3-p13.2) via a polymerase chain reaction (PCR). A real-time qualitative PCR is usually preferred, although semi-quantitative and quantitative evaluations are now available as well. This genetic analysis may be performed either before or after birth. DNA samples prenatally are collected via amniocentesis. Genetic sequencing techniques thus, aid in diagnosing and counseling mothers with affected babies in their current and/ or subsequent pregnancies.

Other disorders that arise from INSR gene mutations include the type-A insulin resistance syndrome and the Rabson-Mendenhall syndrome and these form the differential diagnosis of leprechaunism. All these diseases represent a continuous clinical spectrum, with Donohue syndrome the most severe (patients usually die by the age of 2 years) and Rabson-Mendenhall syndrome being relatively moderate in severity [7] [8]. Type-A insulin resistance syndrome is usually benign, with patients being diagnosed during adolescence.

There is currently no cure for Donohue Syndrome, and treatment focuses on managing symptoms and complications. This may involve a multidisciplinary approach, including endocrinologists, nutritionists, and other specialists. Managing blood sugar levels is a primary concern, often requiring frequent monitoring and dietary adjustments. In some cases, medications may be used to help control insulin levels. Supportive therapies, such as physical and occupational therapy, can aid in managing developmental delays and improving quality of life.

The prognosis for individuals with Donohue Syndrome is generally poor, with many patients not surviving beyond the first few years of life. The severity of symptoms and complications, such as infections and metabolic imbalances, significantly impact life expectancy. However, with early diagnosis and comprehensive care, some patients may live longer. Ongoing research aims to improve understanding and treatment of this challenging condition.

Donohue Syndrome is caused by mutations in the INSR gene, which provides instructions for making the insulin receptor. This receptor is crucial for the body's response to insulin. Mutations in the INSR gene lead to a dysfunctional receptor, resulting in severe insulin resistance. The condition is inherited in an autosomal recessive pattern, meaning both copies of the gene in each cell have mutations. Parents of an affected child typically carry one copy of the mutated gene but do not show symptoms.

Donohue Syndrome is extremely rare, with only a few dozen cases reported worldwide. It affects both males and females equally and occurs in various ethnic groups. Due to its rarity, the exact prevalence is unknown, and it is considered one of the rarest genetic disorders. The condition is often identified in infancy due to its distinct clinical features and severe metabolic disturbances.

The pathophysiology of Donohue Syndrome centers around the body's inability to respond to insulin due to defective insulin receptors. Insulin is a hormone that helps regulate blood sugar levels by facilitating the uptake of glucose into cells. In Donohue Syndrome, mutations in the INSR gene lead to non-functional insulin receptors, preventing glucose from entering cells efficiently. This results in high insulin levels and low blood sugar, causing the various symptoms and complications associated with the disorder.

As a genetic disorder, there is no known way to prevent Donohue Syndrome. Genetic counseling is recommended for families with a history of the condition or those known to carry mutations in the INSR gene. Prenatal testing and carrier screening can provide information about the risk of having a child with the syndrome. Research into gene therapy and other advanced treatments may offer future possibilities for prevention or mitigation.

Donohue Syndrome is a rare genetic disorder characterized by severe insulin resistance and a range of physical and metabolic symptoms. It is caused by mutations in the INSR gene, leading to dysfunctional insulin receptors. While there is no cure, early diagnosis and comprehensive care can help manage symptoms and improve quality of life. The condition is extremely rare, with a poor prognosis, but ongoing research aims to enhance understanding and treatment options.

For patients and families affected by Donohue Syndrome, understanding the condition is crucial. It is a genetic disorder that affects how the body responds to insulin, leading to various symptoms such as growth delays, unusual facial features, and metabolic issues. While there is no cure, treatment focuses on managing symptoms and improving quality of life. Support from a team of healthcare professionals, including genetic counselors, can provide valuable guidance and support.

1. Longo N, Langley SD, Griffin LD, et al. Two mutations in the insulin receptor gene of a patient with leprechaunism: application to prenatal diagnosis. JCEM 1995; 80:1496–1501.
2. Semple RK, Savage DB, Halsall DJ, et al., editors. Syndromes of severe insulin resistance and/or lipodystrophy. Genetic Diagnosis of Endocrine Disorders. London: Elsevier; 2010. 39–52.
3. Donohue WL. Clinical Conference: dysendocrinism. J Pediatr 1948; 32:739–1739.
4. Taylor SI, Arioglu E. Genetically defined forms of diabetes in children. JCEM. 1999; 84:4390–4396.
5. Unal S, Aycan Z, Halsall DJ, et al. Donohue syndrome in a neonate with homozygous deletion of exon 3 of the insulin receptor gene. J Pediatr Endocrinol Metab 2009; 22:669–674.
6. Longo N, Wang Y, Smith SA, et al. Genotype -phenotype correlation in inherited severe insulin resistance. Hum Mol Genet 2002; 11:1465–1475.
7. Semple RK, Savage DB, Cochran EK, et al. Genetic syndromes of severe insulin resistance. Endocrine Reviews 2011; 32:498–514.
8. Ardon O, Procter M, Tvrdik T, et al. Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene. Mol Genet Metab Rep 2014; 1:71–84.