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]

  Donohue syndrome patients are prone to persistent and recurrent infections. Delayed bone growth not only leads to skeletal abnormalities, it also leads to a compromised immune system. [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]

• Collapse

  These children are predisposed to developing cardiomyopathy and therefore at risk of cardiovascular collapse under anesthesia. 2017 John Wiley & Sons Ltd. [ncbi.nlm.nih.gov]

  These children are predisposed to developing cardiomyopathy and therefore at risk of cardiovascular collapse under anesthesia. [pubmed.ncbi.nlm.nih.gov]

• Failure to Thrive

  DS is characterized by pre- and postnatal growth retardation with failure to thrive, lipoatrophy, muscle wasting, acanthosis nigricans, hypertrichosis, and dysmorphic features. [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]

  Dysmorphic features, abnormalities of the craniofacial region, low birth weight, skin abnormalities, abdominal distension and hypertrichosis were observed. [journals.lww.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]

• Continuous Murmur

  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]

• 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]

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

  Note the marked hirsutism, sunken cheeks, pointed chin, large mouth, thick lips, wide nostrils, large eyes, large ears, and enlarged clitoris. Figure 3.91. [rrnursingschool.biz]

• 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]

  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]

  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]

• Large Feet

  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 0004510 Postnatal growth retardation Growth delay as [rarediseases.info.nih.gov]

• Thick Lips

  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]

  Note the marked hirsutism, sunken cheeks, pointed chin, large mouth, thick lips, wide nostrils, large eyes, large ears, and enlarged clitoris. Figure 3.91. [rrnursingschool.biz]

  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]

• Small Face

  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]

  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]

  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]

• 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]

  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]

  Acromegaloid features include gigantism, muscular hypertrophy, advanced bone age, prognathism, prominent orbital ridges, enlarged hands and feet, clitoromegaly, and enlarged external genitalia in males. Hepatomegaly. [ncbi.nlm.nih.gov]

  She has dysmorphic features, including a high arched, V-shaped palate with dysplastic teeth, hirsutism, acanthosis nigricans, breast enlargement and clitoromegaly. A random insulin level was 500 µU/ml, with a simultaneous glucose level of 85 mg/dL. [hmg.oxfordjournals.org]

• 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]

• Uremia

  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]

• 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]

• Visceromegaly

  Abdominal ultrasound scan showed nephrocalcinosis and visceromegaly. [academic.oup.com]

• Biventricular Hypertrophy

  Less common clinical features were also present, such as atrial septal defect and biventricular hypertrophy, clotting disorders, abnormal liver function tests and nephrocalcinosis. [ncbi.nlm.nih.gov]

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]

The prognosis is poor, with most babies dying in infancy. [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]

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]

They are organised into groups, and further divided into clinical, etiological or histopathological sub-types. [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]

[…] 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]

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]

"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]

[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]

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

We discuss how the disease presents, its genetic underpinning, and its prevention. The case was encountered in an Arab male born on 1 September, 2014, for consanguineous parents. [journals.lww.com]

Identification of the causative mutation enables prevention of this devastating disease. Record : found Abstract : found Article : not found The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. [scienceopen.com]

[…] in metabolic control in the event of diabetes and in growth pattern, although variable results have been reported. 11 A multidisciplinary approach to this type of patient is recommended, focusing on optimizing glycemic control, but also on trying to prevent [elsevier.es]

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.