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.

• Recurrent Infection

  Other abnormalities that have been observed in infants with leprechaunism include recurrent infections, abnormalities of the intellect and unusually large hands and feet. [symptoma.com]

  Although some patients survived for several years, most die of severe failure to thrive with recurrent infections in the first year of life. [accessanesthesiology.mhmedical.com]

  Prognosis Individuals born with Donohue syndrome generally die in infancy from either malnutrition or recurrent and persistent infection. [encyclopedia.com]

  infections Frequent infections Frequent, severe infections Increased frequency of infection infections, recurrent Predisposition to infections Susceptibility to infection [ more ] 0002719 Small face Short and narrow face Small facies [ more ] 0000274 [rarediseases.info.nih.gov]

• Nail Abnormality

  Patients with RMS are characterized by coarse facial features, growth retardation, severe acanthosis nigricans, hypertrichosis, dental and nail abnormalities as well as large external genitalia. [karger.com]

• Failure to Thrive

  The clinical course showed failure to thrive, and episodes of alternating hypoglycemia and hyperglycemia. Laboratory tests revealed direct hyperbilirubinemia. [ncbi.nlm.nih.gov]

  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. [symptoma.com]

• Abdominal Distension

  Many of the risks relate to restrictive lung disease and abdominal distension which worsens with bag valve mask ventilation and limited respiratory reserve which leads to precipitous desaturation. [ncbi.nlm.nih.gov]

  A, Abdominal distension, inguinal hernia, large hands and feet, clitoromegaly, and lipohypotrophy. B, Gum and lip hypertrophy, triangular facies, hirsutism, prominent eyes with infraorbital creases, and nipple hypertrophy. [academic.oup.com]

  She had feeding difficulty due to abdominal distension. Thus, continuous enteral feeding which also decreased the frequency of hypoglycemic episodes was started. [karger.com]

• Abdominal Pain

  A 14-year-old girl, whose parents were consanguineous, was often admitted for abdominal pain over the past 8 years. [ncbi.nlm.nih.gov]

• Photophobia

  Cockayne Syndrome: DNA repair syndrome characterized by short stature, premature aging, and photophobia, which is aggravated by UV exposure but has no link to cancer development. [accessanesthesiology.mhmedical.com]

• Hirsutism

  Clinical features include severe intrauterine and postnatal growth restriction, characteristic dysmorphic FACIES; HIRSUTISM; VIRILIZATION; multiple endocrine abnormalities, and early death. [profiles.umassmed.edu]

  The patient is a Japanese boy with acanthosis nigricans, lack of subcutaneous fat, hirsutism, thick lips, gum hypertrophy and extremely high insulin levels (6702 mU/mL). [jstage.jst.go.jp]

  We describe a new case of Donohue syndrome born at 37 weeks' gestation of unrelated parents and presented with intra-uterine growth retardation, nipple hypertrophy, macropenis, distended abdomen, hirsutism and dysmorphic features. [ncbi.nlm.nih.gov]

  At a glance It is an extremely rare inherited condition caused by resistance to insulin with growth deficiency and characterized by dysmorphic facies (“elfin-like”), severe growth retardation, hirsutism, and multiple endocrine disorders. [accesspediatrics.mhmedical.com]

• Large Hand

  A, Abdominal distension, inguinal hernia, large hands and feet, clitoromegaly, and lipohypotrophy. B, Gum and lip hypertrophy, triangular facies, hirsutism, prominent eyes with infraorbital creases, and nipple hypertrophy. [academic.oup.com]

  Other abnormalities that have been observed in infants with leprechaunism include recurrent infections, abnormalities of the intellect and unusually large hands and feet. [symptoma.com]

  hands large hand 0001176 Long foot Disproportionately large feet large feet long feet [ more ] 0001833 Low-set ears Low set ears Lowset ears [ more ] 0000369 Nail dysplasia Atypical nail growth 0002164 Ovarian cyst 0000138 Pancreatic islet- cell hyperplasia [rarediseases.info.nih.gov]

  Infants with leprechaunism may have additional abnormalities, including intellectual disability, abnormally large hands and feet, an unusually widened (dilated) or enlarged (distended) stomach, abnormal amounts of iron in the liver, and/or stoppage of [rarediseases.org]

  As an additional side effect of the increased sex hormones released in Donohue syndrome, these individuals often have extremely large hands and feet relative to their non-affected peer group. [encyclopedia.com]

• Large Feet

  […] hands large hand 0001176 Long foot Disproportionately large feet large feet long feet [ more ] 0001833 Low-set ears Low set ears Lowset ears [ more ] 0000369 Nail dysplasia Atypical nail growth 0002164 Ovarian cyst 0000138 Pancreatic islet- cell hyperplasia [rarediseases.info.nih.gov]

• Thick Lips

  She appeared markedly emaciated, and had hirsuitism, thickened skin with patchy hyperpigmentation, coarse facial features, sunken cheeks, pointed chin, flared nostrils, broad open mouth, thick lips, low-set ears, enlarged breasts and clitoromegaly. [indianpediatrics.net]

  The patient is a Japanese boy with acanthosis nigricans, lack of subcutaneous fat, hirsutism, thick lips, gum hypertrophy and extremely high insulin levels (6702 mU/mL). [jstage.jst.go.jp]

  Almost no cases survive beyond early infancy (under 3 years). elfin facial features enlarged ears which are set low a flattened nose thick lips orbital hypertelorism endocrine disturbances severe growth retardation altered carbohydrate metabolism, postprandial [radiopaedia.org]

  Facial features indicative of Leprechaunism include protuberant and low-set ears, flaring nostrils, and thick lips. [wikidoc.org]

  The patient showed typical "elfin-like" face with wide nostrils and thick lips, large and low-set ears, and dysplastic nails. The areola showed a yellowish thickened plaque of 5-cm diameter that corresponded to a hyperplasia of the sebaceous glands. [ncbi.nlm.nih.gov]

• Small Face

  Signs and symptoms include failure to thrive, limited growth, alopecia, wrinkled skin, small face, development of atherosclerosis, and heart disease. There is no cure for this condition. [icd10data.com]

  face Short and narrow face Small facies [ more ] 0000274 Wide mouth Broad mouth Large mouth [ more ] 0000154 Showing of 61 | Last updated: 5/1/2019 Making a diagnosis for a genetic or rare disease can often be challenging. [rarediseases.info.nih.gov]

  At birth, the infant was noted to have dysmorphic features, such as a small face with prominent eyes and thick lips, large, pointed ears, depressed nasal bridge, wide nostrils, absence of subcutaneous fat, wrinkled and loose skin, hirsutism, acanthosis [hmg.oxfordjournals.org]

• Frontal Bossing

  De Barsy Moens Diercks Syndrome: Autosomal recessive disorder featuring cutis laxa, frontal bossing and prominent ears, athetosis, cloudy cornea, hypotonia and hyperlaxity of joints, and/or short stature. [accessanesthesiology.mhmedical.com]

• Clitoromegaly

  She appeared markedly emaciated, and had hirsuitism, thickened skin with patchy hyperpigmentation, coarse facial features, sunken cheeks, pointed chin, flared nostrils, broad open mouth, thick lips, low-set ears, enlarged breasts and clitoromegaly. [indianpediatrics.net]

  A, Abdominal distension, inguinal hernia, large hands and feet, clitoromegaly, and lipohypotrophy. B, Gum and lip hypertrophy, triangular facies, hirsutism, prominent eyes with infraorbital creases, and nipple hypertrophy. [academic.oup.com]

  However, other clinical findings, such as growth retardation, clitoromegaly, dysmorphic facial appearance and dental abnormalities observed in RMS were not present in our case. [karger.com]

  Dental abnormalities, enlarged phallus in males, clitoromegaly in females, nephromegaly, nephrocalcinosis, paradoxical fasting hypoglycemia, postprandial hyperglycemia, severe insulin resistance and hyperinsulinemia are other associated findings. [ 7 [ijpeonline.biomedcentral.com]

• Polyuria

  In addition, the patient developed polyuria and uremia despite normal creatinine levels, hypernatremia, and hypertension. To our knowledge, these metabolic derangements were not previously reported in patients with DS. [ncbi.nlm.nih.gov]

  Case presentation An 11 year old boy from a rural area in Sri Lanka presented to us with polyuria, polydipsia of one year duration and intermittent headache of one month duration. [ijpeonline.biomedcentral.com]

• Amenorrhea

  Some women present with oligomenorrhea, amenorrhea, or features of polycystic ovary syndrome. [ncbi.nlm.nih.gov]

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.

• Delayed Bone Age

  Most infants with leprechaunism exhibit delayed growth before and after birth (pre- and postnatal growth deficiency), delayed bone age or maturation. [rarediseases.org]

We consider that the rhIGF1 treatment contributed to his long survival, but it was not able to prevent his diabetic condition. Our report provides important insights into the function of INSR, and for the treatment of leprechaunism. [jstage.jst.go.jp]

The large neovascularization of the disk regressed after treatment with argon laser panretinal photocoagulation. Five years after treatment, the patient maintained good vision. [ncbi.nlm.nih.gov]

In view of the poor prognosis and young age, this patient was given symptomatic treatment. She succumbed to pneumonia and septicemia by 6 months of age. Fig. 1 Hirsuitism, marked emaciation and coarse facial features in Leprechaunism. [indianpediatrics.net]

The prognosis is poor, with most babies dying in infancy. [ncbi.nlm.nih.gov]

Prognosis Prognosis is uncertain, growth is severely affected and life expectancy rarely exceeds a few months. The documents contained in this web site are presented for information purposes only. [orpha.net]

Etiology The syndrome is associated with homozygous or compound heterozygous mutations in the insulin receptor gene ( INSR ; 19p13.3-p13.2). Diagnostic methods A positive diagnosis requires identification of one mutation in each allele of this gene. [orpha.net]

It is hoped that recent advancements in the genetic etiologies of common diseases will improve pharmaceutical development ... [liquisearch.com]

Etiologic diagnosis and behaviour when confronted with abnormal hair growth in a child. Ann Dermatol Venereol. 2002;129:817-20. Longo N, Wang Y et al. Genotype-phenotype correlation in inherited severe insulin resistance. [malattierare.regione.veneto.it]

Brugada syndrome is genetically determined and has an autosomal dominant pattern of transmission in about 50% of familial cases (see Etiology). [emedicine.medscape.com]

Summary Epidemiology It is a very rare condition with less than 1 case in every million births. [orpha.net]

Epidemiology[edit] Donohue syndrome is an extremely rare disorder that occurs in one of every million births worldwide. [en.wikipedia.org]

[…] collaborate analysis of diabetic criteria in AsiaDECODA研究 Diabetes epidemiology collaborate analysis of diabetic criteria in EuropeDECODE研究 Diabetes epidemiology research internationalDERI研究 Diabetes mellitus due to other specific mechanisms or disease [jds.or.jp]

Pathophysiology The primary defect in leprechaunism is located in the insulin receptor, but a secondary associated defect probably is responsible for growth failure because of an impaired response to endogenous growth hormone. [accesspediatrics.mhmedical.com]

[citation needed] Pathophysiology[edit] The cause of the disease is the lack of a fully functional insulin receptor, which has a profound effect during fetal development and thereafter. [en.wikipedia.org]

"Brugada" syndrome: clinical data and suggested pathophysiological mechanism. Circulation. 1999 Feb 9. 99(5):666-73. [Medline]. Meregalli PG, Wilde AA, Tan HL. [emedicine.medscape.com]

Why diagnose monogenic diabetes  To elucidate the pathophysiology  Changes the treatment  diagnosis has implications for other family members often correcting their diagnosis, prognosis and treatment as well as allowing appropriate genetic counselling [slideshare.net]

We report the clinical, molecular, and biochemical characterization of three new patients with DS, and address genotype–phenotype issues playing a role in the pathophysiology of DS. [scienceopen.com]

We consider that the rhIGF1 treatment contributed to his long survival, but it was not able to prevent his diabetic condition. Our report provides important insights into the function of INSR, and for the treatment of leprechaunism. [jstage.jst.go.jp]

CONCLUSION: According to the present case report, close monitoring of blood glucose as well as caring to prevent infection and sepsis is recommended. Keywords: Leprechaunism, Donohue Syndrome, Insulin Resistance, Craniofacial Abnormalities. [jbums.org]

Except for very short surgeries, regular blood glucose measurements should be performed and a dextrose-containing intravenous solution administered to detect and prevent hypoglycemia, respectively. [accessanesthesiology.mhmedical.com]

Donohue syndrome results from a mutation of the insulin receptor gene which prevents insulin in the blood from being processed. [encyclopedia.com]

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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.
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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.
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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.