Edit concept Question Editor Create issue ticket

Donohue Syndrome

Donahue's Syndrome

Donohue syndrome, also known as leprechaunism, is a rare autosomal recessive disorder characterized by extreme insulin resistance, growth delays and dysmorphic facies.


Presentation

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]
  • 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]
Aspiration
  • If required, bag valve mask ventilation should be accompanied by constant gastric aspiration. Intubation is challenging, and a difficult airway plan, including a second experienced anesthetist and ENT support, should be in place.[ncbi.nlm.nih.gov]
Overeating
  • A 14-year-old girl, whose parents were consanguineous, was often admitted for abdominal pain over the past 8 years.[ncbi.nlm.nih.gov]
  • Elsevier Health Sciences, ٢٥‏/٠٢‏/٢٠١٥ - 2700 من الصفحات Considered the definitive source in its field for over 35 years, Endocrinology: Adult and Pediatric, has been thoroughly updated to reflect today's recent advances in adult and pediatric endocrinology[books.google.com]
  • Save over 20% compared to the individual article price.[karger.com]
  • Over 50 insulin receptor mutations have been described which result in profound insulin resistance and altered glucose homeostasis with fasting hypoglycemia and postprandial hyperglycemia. Almost all affected patients die before two years of age.[indianpediatrics.net]
  • Over 40 distinct mutations of this gene have been identified.[encyclopedia.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]
  • Dysmorphic features, abnormalities of the craniofacial region, low birth weight, skin abnormalities, abdominal distension and hypertrichosis were observed.[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]
Large Hand
  • 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]
  • 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]
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]
  • 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]
  • 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).[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]
  • The physical features most often associated with this condition include hypertrichosis, pachyderma, acanthosis nigricans, prominent genitalia, and elfin-like facial characteristics of prominent eyes, wide nostrils, thick lips, and large, low-set ears.[journals.lww.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]
  • 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]
  • 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]
  • 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]

Workup

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]

Treatment

  • 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]
  • 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]
  • Limited treatment options exist for patients with DS. The use of continuous rhIGF-1 via an insulin pump may be a viable option, although further experience is needed to establish safety and efficacy.[ncbi.nlm.nih.gov]
  • Treatment is challenging and often unsuccessful, and relies on maintaining normoglycaemia and avoiding fasting; in some patients, recombinant human insulin-like growth factor (rhIGF-1) has been trialled.[ncbi.nlm.nih.gov]
  • Currently, treatment with recombinant insulin-like growth factor 1 demonstrates effectiveness, and a combination treatment with insulin-like growth factor binding protein 3 resulted in an increased lifespan.There is a scarcity of genetic information on[ncbi.nlm.nih.gov]

Prognosis

  • The prognosis is poor, with most babies dying in infancy.[ncbi.nlm.nih.gov]
  • Prognosis is poor with the majority of patients dying in infancy of sepsis.[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]
  • The severity of the disease and phenotype is determined by the severity of the mutations, with impaired receptor function being associated with a poorer prognosis and a decreased chance of survival. 6 A wide genetic heterogeneity exists, and multiple[elsevier.es]

Etiology

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

Epidemiology

  • 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]
  • […] which can lead to permanent injuries, life-threatening complications, and death, 1 , 13 with the latter occurring in 6% to 10% of cases of FI 13 (and higher percentages in the case of poisoning). 14 The incidence of FI in children 2 , 7 , 15 However, epidemiologic[pediatrics.aappublications.org]
Sex distribution
Age distribution

Pathophysiology

  • 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 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]
  • The pathophysiology of RMS is explained by abnormality of the INSR gene at the gene map locus 19p13.2. (OMIM: 609968, 246200, 262190) resulting in severe biallelic loss-of-function of the insulin receptor and impaired insulin binding [ 3, 5 ].[ijpeonline.biomedcentral.com]

Prevention

  • 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]
  • 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]
  • […] programDPP試験 Diabetes prevention trial-1DPT-1試験 Diabetes prevention trial-Type 1DPT-1試験 Diabetic nephropathy remission and regression team trial in JapanDNETT-Japan Diabetic retinopathy candesartan trialsDIRECT試験 Donohue's syndromeドナヒュー症候群 Duloxetine[jds.or.jp]

References

Article

  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.

Ask Question

5000 Characters left Format the text using: # Heading, **bold**, _italic_. HTML code is not allowed.
By publishing this question you agree to the TOS and Privacy policy.
• Use a precise title for your question.
• Ask a specific question and provide age, sex, symptoms, type and duration of treatment.
• Respect your own and other people's privacy, never post full names or contact information.
• Inappropriate questions will be deleted.
• In urgent cases contact a physician, visit a hospital or call an emergency service!
Last updated: 2018-06-22 07:54