Continuous subcutaneous IGF-1 therapy via insulin pump in a patient with Donohue syndrome

Weber, David R.; Stanescu, Diana E.; Semple, Robert K.; Holland, Cheryl; Magge, Sheela N.

doi:10.1515/jpem-2013-0402

Cited by 19 publications

(22 citation statements)

References 26 publications

(30 reference statements)

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“…Consanguineous mating is a unique form of union, which may lead to genetic detrimental effects as a consequence of homozygosity of harmful genes. The increased frequency of homozygous genotypes allowed the less common alleles to become manifested homozygous, 34 thus descendants of consanguineous parents have higher susceptibility to congenital malformation 35 , 36 neonatal, postneonatal, and infant mortality than those of unrelated parents. 37 – 41 …”

Section: Discussionmentioning

confidence: 99%

Classic Case Report of Donohue Syndrome (Leprechaunism; OMIM *246200)

et al. 2016

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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.

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Section: Discussionmentioning

confidence: 99%

Classic Case Report of Donohue Syndrome (Leprechaunism; OMIM *246200)

et al. 2016

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“…Furthermore, although perturbed androgen metabolism has been suggested to play an important role in PCOS in some forms of IR (85), the severe PCOS seen in generalised lipodystrophy argues that adipose androgen is not an obligate link between severe IR and PCOS. In Donohue syndrome, cystic ovarian enlargement may be seen in infancy, and this can be massive even when no functional insulin receptors are expressed (86,87). While this ovarian pathology is not identical to that of PCOS, it is plausible to suggest that it shares the same underlying mechanism, namely, synergic stimulation of follicles by extremely elevated insulin and the gonadotrophins which are elevated in the early months of life before secondary suppression.…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

“…Indeed, several non-malignant elements of the severe IR syndrome, namely, the dermal and epidermal hyperplasia of acanthosis nigricans, the organomegaly of infantile receptoropathy and the pseudo-acromegaloid soft tissue overgrowth common to many forms of IR, attest to the tissue growth-promoting effects of hyperinsulinaemia. In the most severe hyperinsulinaemia seen in Donohue syndrome, ovarian tumours may arise in infancy (86,87), while colonic polyposis is also sometimes seen in either recessive or dominant insulin receptoropathies. Thus, while syndromes of severe IR, except those featuring an underlying defect in DNA damage repair such as Werner and Bloom syndromes, are not penetrant cancer predisposition syndromes, the mitogenic consequences of sustained severe hyperinsulinaemia are apparent, and this adds weight to the notion of a role for hyperinsulinaemia per se in increasing prevalent cancer risk.…”

Section: Does Ir Cause Cancer?mentioning

confidence: 99%

EJE PRIZE 2015: How does insulin resistance arise, and how does it cause disease? Human genetic lessons

Semple¹

2016

European Journal of Endocrinology

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Insulin orchestrates physiological responses to ingested nutrients; however, although it elicits widely ramifying metabolic and trophic responses from diverse tissues, 'insulin resistance (IR)', a pandemic metabolic derangement commonly associated with obesity, is usually defined solely by blunting of insulin's hypoglycaemic effect. Recent study of monogenic forms of IR has established that biochemical subphenotypes of IR exist, clustering into those caused by primary disorders of adipose tissue and those caused by primary defects in proximal insulin signalling. IR is often first recognised by virtue of its associated disorders including type 2 diabetes, dyslipidaemia (DL), fatty liver and polycystic ovary syndrome (PCOS). Although these clinically observed associations are confirmed by cross-sectional and longitudinal population-based studies, causal relationships among these phenomena have been more difficult to establish. Single gene IR is important to recognise in order to optimise clinical management and also permits testing of causal relationships among components of the IR syndrome using the principle of Mendelian randomisation. Thus, where a precisely defined genetic defect is identified that directly produces one component of the syndrome, then phenomena that are causally linked to that component should be seen. Where this is not the case, then a simple causal link is refuted. This article summarises known forms of monogenic severe IR and considers the lessons to be learned about the pathogenic mechanisms both upstream from common IR and those downstream linking it to disorders such as DL, fatty liver, PCOS and cancer.

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“…Учитывая гомологичное строение рецепторов инсулина и ИФР-1, рядом авторов [23][24][25][26] проде-монстрировано улучшение весо-ростовых показате-лей, снижение уровня HbA 1c и увеличение продол-жительности жизни у пациентов с синдромом Дона-хью при применении рекомбинантного ИФР-1 (рИФР-1) как отдельно, так и в сочетании с реком-бинантным ИФРСБ3 (рИФРСБ3). Наибольшая на сегодняшний день продолжительность жизни на фоне терапии рИФР-1 (24 года) была описана япон-скими авторами в 2013 г.…”

Section: Discussionunclassified