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]

• Weakness

  In Marfan syndrome, the aorta can stretch and grow weak. في متلازمة مارفان، الاورطى يمكن أن يتمدد وينمو ضعيفا. In tunnel syndrome, pain occurs when lifting the arms up. في متلازمة النفق، يحدث الألم عند رفع الذراعين لأعلى. [context.reverso.net]

  People are weak, and there is so much to do. At just seventeen she marries and moves down into the valley of Gap Creek, where perhaps life will be better. [play.google.com]

  INTRODUCTION The most common forms of diabetes mellitus are due to insulin resistance, for example, a reduced or weak response to the effects of insulin beyond its receptor. [journals.lww.com]

  Novel subtype of congenital generalized lipodystrophy associated with muscular weakness and cervical spine instability. Am J Med Genet A. 2008; 146A :2318–26. [ PMC free article : PMC2716114 ] [ PubMed : 18698612 ] Tsoukas MA, Farr MF, Mantzoros CS. [ncbi.nlm.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]

• Dentist

  In addition, among other things, she needs hours of stimulation and physiotherapy, a special diet, a dentist and other specialist doctors and the adaptation of her home. [bilbaoport.eus]

• 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]

• 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]

  Physical examination showed genitomegaly, lipoatrophy (A), abdominal distension, dermal disorders and huge depressed ears with elfin facies (B). [panafrican-med-journal.com]

• Polydipsia

  She presented not only polydipsia, polyphagia, and weight loss but also small elfin face, distended abdomen, enlarged clitoris, hypertrichosis, acanthosis nigricans of the neck, decreased subcutaneous fat and 3/6 continuous murmur radiating to the right [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]

• 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]

• Hirsutism

  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]

  B, Gum and lip hypertrophy, triangular facies, hirsutism, prominent eyes with infraorbital creases, and nipple hypertrophy. C, Hypertrichosis and acanthosis nigricans. [academic.oup.com]

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

• Short Arm

  Donohue syndrome, a rare autosomal recessive disorder, is associated with the mutation of the insulin receptor gene in the short arm of the 19th chromosome. [ncbi.nlm.nih.gov]

  The mutations responsible for Leprechaunism are found on the short arm chromosome 19 (19p13.2) within the coding sequence of the INSR gene (insulin receptor) causing the production of inactive receptor molecules. [wikidoc.org]

  This alteration is due to mutations in the gene INSR, located on the short arm of chromosome 19 (19p13.3-p13.2). This gene encodes a protein called insulin receptor, which is found in many cell types. [ivami.com]

  The mutations responsible for the disorder are found on the short arm chromosome 19 (19p13.2) within the coding sequence of the INSR gene ( insulin receptor ) causing the production of inactive receptor molecules. [liquisearch.com]

  The mutations responsible for the disorder are found on the short arm chromosome 19 (19p13.2) within the coding sequence of the INSR gene (insulin receptor) causing the production of inactive receptor molecules. [flipper.diff.org]

• 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]

  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]

• Decrease in Height

  […] body height Small stature [ more ] 0004322 Skeletal muscle atrophy Muscle degeneration Muscle wasting [ more ] 0003202 Thick lower lip vermilion Increased volume of lower lip Plump lower lip Prominent lower lip [ more ] 0000179 Thick nasal alae 0009928 [rarediseases.info.nih.gov]

• Thick Lips

  We report a 5 day old neonate with refractory hyperglycemia and paradoxical hypoglycemia, severe intrauterine growth retardation, typical 'elfin' facies (hypertrichosis, large and low-set ears, broad nasal tip, flared nares, thick lips), reduced subcutaneous [ncbi.nlm.nih.gov]

  Facial features indicative of Donohue syndrome include protuberant and low-set, flaring, and thick lips. Physical features include stunted growth (including during ), an enlarged and in affected, and an enlarged in affected males. [sapnaonline.com]

  a rare hereditary disorder of extreme insulin resistance that is characterized especially by intrauterine and postnatal growth retardation, skin abnormalities, hirsutism, emaciation, widely spaced eyes, thick lips, low-set ears, and enlarged genitalia [merriam-webster.com]

• 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 [doi.org]

• Clitoromegaly

  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 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]

  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. [ncbi.nlm.nih.gov]

Transplantation 765 65 Treatment of Diabetes in the Hospitalized Patient 1103 66 The Diabetic Foot Strategies for Treatment 1111 BIOLOGY OF THE COMPLICATIONS OF DIABETES 793 67 Vascular Disease of the Lower Extremities 1123 Cameron M Akbari and Frank [books.google.com]

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]

It may be that this is a milder type of leprechaunism with a better prognosis, perhaps caused by a different type of mutation from those previously described. [doi.org]

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]

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

[…] 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]

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

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]

"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]

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]

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]

[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]

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. [ncbi.nlm.nih.gov]

But prevention helps exist and help to fight against this syndrome. ولكن وسائل الوقاية موجوده، وتساعد على محاربة هذه المتلازمة. Babies born with Hunter syndrome almost always appear healthy at birth. [context.reverso.net]

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]

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

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.