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Medicine Feb 2016Donohue syndrome ([DS]; leprechaunism) describes a genetic autosomal recessive disorder that results from the presence of homozygous or compound heterozygous mutations...
Donohue syndrome ([DS]; leprechaunism) describes a genetic autosomal recessive disorder that results from the presence of homozygous or compound heterozygous mutations in the insulin receptor gene (INSR; 19p13.3-p13.2).Donohue syndrome is associated with a fatal congenital form of dwarfism with features of intrauterine and postnatal growth retardation, exaggerated hyperglycemia with hyperinsulinism and dysmorphic abnormalities.We present a case of DS owing to the rarity of this syndrome (1 case in every million births). 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. The delivery was via cesarean section at 37 weeks gestation due to severe intrauterine growth restriction and nonprogress labor term. The patient was admitted to the Neonatal Intensive Care Unit due to infection, and jaundice. Dysmorphic features, abnormalities of the craniofacial region, low birth weight, skin abnormalities, abdominal distension and hypertrichosis were observed. Laboratory examinations showed, hyperinsulinism, increased C-peptide, thrombocytopenia, leucopenia, and anemia.The diagnosis of DS was done based on the combinations of typical dysmorphic characteristics, clinical evaluation, supported by genetic analysis and exaggerated biochemical results. Genetic diagnosis of DS was performed through analysis of DNA via polymerase chain reaction (PCR). A qualitative real-time PCR was used, to monitor the amplification of a targeted DNA molecule during the PCR. Other technique using sequencing of the INSR gene, which permits genetic diagnosis, counseling, and antenatal diagnoses in subsequent pregnancies, were also performed.Treatment of DS is supportive and requires the combined efforts of a multidisciplinary team, which include pediatricians, endocrinologists, dermatologists, and other health care professionals. 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 DS among the Arab population. Consanguinity is one of underlying reasons for the appearance of rare genetic disorders. Inbreeding has long been considered a controversial phenomenon. Genetic counseling and overwhelming the alertness of the negative consequences of consanguinity on public health are warranted.
Topics: Consanguinity; Donohue Syndrome; Fatal Outcome; Humans; Infant; Infant, Newborn; Male
PubMed: 26871809
DOI: 10.1097/MD.0000000000002710 -
Acta Chirurgiae Plasticae 1972
Topics: Abnormalities, Multiple; Dwarfism; Female; Humans; Infant; Intellectual Disability; Lipodystrophy; Progeria
PubMed: 4112399
DOI: No ID Found -
American Journal of Clinical Pathology May 1966
Topics: Dwarfism, Pituitary; Humans; Hyperplasia; Infant; Male; Pituitary Diseases; Progeria
PubMed: 5939954
DOI: 10.1093/ajcp/45.5.614 -
Journal of Pediatric Endocrinology &... Jul 2009Donohue syndrome describes the clinical consequences of the most severe genetic loss of insulin receptor function. The cardinal features are severe linear growth...
Donohue syndrome describes the clinical consequences of the most severe genetic loss of insulin receptor function. The cardinal features are severe linear growth impairment pre- and postnatally with abnormal glucose metabolism and a characteristic pattern of soft tissue overgrowth. 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 fat, distended abdomen, and enlarged external genitalia and nipples. Fasting serum insulin and C-peptide were severely elevated at >2,100 pmol/l and >2,331 pmol/l, respectively. In addition, hepatic, ovarian and renal enlargement was demonstrated by ultrasonography. The neonate died within two months secondary to hypoglycemia. Diplex PCR analysis of the insulin receptor gene revealed the neonate to be homozygous for deletion of exon 3. Both parents were heterozygous for this deletion but were metabolically healthy. As such a deletion has previously been reported in Israel, we suggest that it may show a founder effect in the Middle East.
Topics: Abnormalities, Multiple; Blood Glucose; Exons; Fatal Outcome; Female; Fetal Growth Retardation; Gene Deletion; Homozygote; Humans; Hyperglycemia; Hypoglycemia; Infant, Newborn; Insulin Resistance; Receptor, Insulin; Syndrome
PubMed: 19774849
DOI: 10.1515/jpem.2009.22.7.669 -
Optometry and Vision Science : Official... May 2003Donohue's syndrome, also known as Leprechaunism, is a rare autosomal recessive disease that manifests at birth with symptoms of endocrine dysfunction. Metabolic...
INTRODUCTION
Donohue's syndrome, also known as Leprechaunism, is a rare autosomal recessive disease that manifests at birth with symptoms of endocrine dysfunction. Metabolic characteristics of the disease include postprandial hyperglycemia, fasting hypoglycemia, insulin resistance, hyperinsulinemia, and failure to thrive. 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. Not only is this syndrome rare, but it often results in infant and early childhood mortality. The literature regarding ocular manifestations is limited.
CASE REPORT
We present a case of a 29-year-old male with Donohue's syndrome and significant ocular findings including a subluxated mature cataract, retinal detachment, high myopia, and optic atrophy.
DISCUSSION
These ocular sequelae are discussed with regard to the noted endocrine dysfunction and its effects on tissue development and growth.
Topics: Abnormalities, Multiple; Adult; Cataract; Endocrine System Diseases; Eye Diseases; Face; Genitalia, Male; Humans; Hyperglycemia; Hyperinsulinism; Hypertelorism; Insulin Resistance; Lens Subluxation; Male; Myopia; Optic Atrophy; Retinal Detachment; Syndrome
PubMed: 12771659
DOI: 10.1097/00006324-200305000-00008 -
Indian Journal of Pediatrics 1980
Topics: Abnormalities, Multiple; Humans; Infant; Lipodystrophy; Syndrome
PubMed: 7450836
DOI: 10.1007/BF02822886 -
Pediatric Diabetes Jun 2018The main biochemical hallmark of the rare and lethal condition of Donohue syndrome (DS) is hyperinsulinemia. The roles of the gut and other pancreatic hormones involved...
The main biochemical hallmark of the rare and lethal condition of Donohue syndrome (DS) is hyperinsulinemia. The roles of the gut and other pancreatic hormones involved in glucose metabolism, satiety and energy expenditure have not been previously reported in DS. Two siblings with genetically confirmed DS and extremely low weight underwent a mixed meal (MM) test where pancreatic hormones insulin, C-peptide, glucagon, active amylin, pancreatic polypeptide (PP) as well as gut hormones active glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), ghrelin, peptide YY (PYY) and leptin were analyzed using a Multiplex assay. Results were compared to those of 2 pediatric controls. As expected, concentrations of insulin, C-peptide and amylin were very high in DS cases. The serum glucagon concentration was undetectable at the time of hypoglycemia. GIPs concentrations were lower in the DS, however, this was not mimicked by the other incretin, GLP-1. Ghrelin concentrations were mainly undetectable (<13.7 pg/mL) in all participants. DS cases had higher PYY and dampened PP concentrations. Leptin levels remained completely undetectable (<137.0 pg/mL). Patients with DS have extremely high amylin levels, completely undetectable serum glucagon and leptin levels with abnormal satiety regulating hormone PP with a relatively normal ghrelin response during a MM test. The low serum GIP might be acting as physiological brake on insulin secretion. The undetectable serum leptin levels suggest the potential of using leptin analogues as therapy for DS patients.
Topics: Antigens, CD; Case-Control Studies; Child, Preschool; Donohue Syndrome; Gastrointestinal Hormones; Humans; Infant; Leptin; Male; Mutation, Missense; Polymorphism, Single Nucleotide; Receptor, Insulin; Siblings
PubMed: 29226618
DOI: 10.1111/pedi.12619 -
Diabetes Care May 1991To evaluate renal structure in a child with Donohue syndrome (leprechaunism), who at 10 yr of age was noted to have hypertension, microalbuminuria, and enlarged kidneys,...
OBJECTIVE
To evaluate renal structure in a child with Donohue syndrome (leprechaunism), who at 10 yr of age was noted to have hypertension, microalbuminuria, and enlarged kidneys, a renal biopsy was performed.
RESEARCH DESIGN AND METHODS
The renal biopsy tissue was evaluated by light and electron microscopy with standard stereological techniques to measure glomerular volume, glomerular basement membrane width, fractional mesangial volume, and peripheral capillary filtering surface density.
RESULTS
On renal biopsy, there was a marked increase in glomerular volume, glomerular basement width, and mesangial volume, findings similar to those seen in patients with diabetic nephropathy.
CONCLUSIONS
This patient with marked insulin resistance associated with Donohue syndrome demonstrates renal and glomerular enlargement and morphometric glomerular changes similar to those seen in patients with diabetic nephropathy. In unusual syndromes with hyperglycemia and hyperinsulinemia, renal structural and functional changes typical of traditional diabetes mellitus may be seen.
Topics: Adolescent; Basement Membrane; Capillaries; Child; Developmental Disabilities; Female; Glomerular Mesangium; Humans; Hypertension; Insulin Resistance; Kidney Glomerulus; Renal Circulation; Syndrome
PubMed: 1711953
DOI: 10.2337/diacare.14.5.413 -
The British Journal of Surgery Dec 2021This study aimed to determine the impact of pulmonary complications on death after surgery both before and during the severe acute respiratory syndrome coronavirus 2... (Comparative Study)
Comparative Study
BACKGROUND
This study aimed to determine the impact of pulmonary complications on death after surgery both before and during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic.
METHODS
This was a patient-level, comparative analysis of two, international prospective cohort studies: one before the pandemic (January-October 2019) and the second during the SARS-CoV-2 pandemic (local emergence of COVID-19 up to 19 April 2020). Both included patients undergoing elective resection of an intra-abdominal cancer with curative intent across five surgical oncology disciplines. Patient selection and rates of 30-day postoperative pulmonary complications were compared. The primary outcome was 30-day postoperative mortality. Mediation analysis using a natural-effects model was used to estimate the proportion of deaths during the pandemic attributable to SARS-CoV-2 infection.
RESULTS
This study included 7402 patients from 50 countries; 3031 (40.9 per cent) underwent surgery before and 4371 (59.1 per cent) during the pandemic. Overall, 4.3 per cent (187 of 4371) developed postoperative SARS-CoV-2 in the pandemic cohort. The pulmonary complication rate was similar (7.1 per cent (216 of 3031) versus 6.3 per cent (274 of 4371); P = 0.158) but the mortality rate was significantly higher (0.7 per cent (20 of 3031) versus 2.0 per cent (87 of 4371); P < 0.001) among patients who had surgery during the pandemic. The adjusted odds of death were higher during than before the pandemic (odds ratio (OR) 2.72, 95 per cent c.i. 1.58 to 4.67; P < 0.001). In mediation analysis, 54.8 per cent of excess postoperative deaths during the pandemic were estimated to be attributable to SARS-CoV-2 (OR 1.73, 1.40 to 2.13; P < 0.001).
CONCLUSION
Although providers may have selected patients with a lower risk profile for surgery during the pandemic, this did not mitigate the likelihood of death through SARS-CoV-2 infection. Care providers must act urgently to protect surgical patients from SARS-CoV-2 infection.
Topics: Abdominal Neoplasms; Aged; COVID-19; Cohort Studies; Elective Surgical Procedures; Female; Humans; Male; Middle Aged; Pandemics; Postoperative Complications; Respiration, Artificial; Respiratory Distress Syndrome
PubMed: 34871379
DOI: 10.1093/bjs/znab336 -
Endocrine Journal 2013Leprechaunism (Donohue syndrome) is the most severe type of insulin receptor (INSR) gene anomaly with the majority of patients surviving for only 2 years. We report a...
Leprechaunism (Donohue syndrome) is the most severe type of insulin receptor (INSR) gene anomaly with the majority of patients surviving for only 2 years. We report a surviving 2 -year-old male with leprechaunism, bearing novel compound heterozygous mutations in the INSR. 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). He was as having identified novel compound heterozygous mutations in INSR (p.T910M and p. E1047K). At 24 day-old, recombinant human insulin-like growth factor 1 (rh-IGF1) treatment was started because of poor weight gain. At 2 years old, the patient's serum glucose level and HbA1C value had worsened, and both a bolus of rh-IGF-1 and a subcutaneous injection of a rapid-acting insulin analog after meals, in addition to α-glycosidase inhibitor, were initiated from 2 years onward. Oxygen administration and biphasic positive airway pressure treatment were also initiated from 2 years old due to upper airway obstruction with adenoidal hypertrophy. In the experiments conducted using COS7 cells homozygously transfected with the INSR mutation, T910M INSR failed to process the proreceptor and decreased insulin-stimulated tyrosine phosphorylation. E1047K INSR resulted in a complete absence of insulin-stimulated tyrosine phosphorylation. These findings suggest the near absence of INSR in this patient. 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.
Topics: Child, Preschool; Donohue Syndrome; Humans; Hypoglycemic Agents; Infant; Insulin, Short-Acting; Insulin-Like Growth Factor I; Male; Mutation; Receptor, Insulin; Recombinant Proteins
PubMed: 22972224
DOI: 10.1507/endocrj.ej12-0289