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

Abstract

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.

Clinical characteristics of adolescent cases with Type A insulin resistance syndrome caused by heterozygous mutations in the β‐subunit of the insulin receptor (INSR) gene

“…All INSR mutations in the patients in the present study were located in the TK domain of the β‐subunit, which contains 278 residues (from residue 1023 to residue 1290), which confirms previous reports that INSR mutations in the TK domain impair INSR activity more critically than those located in other domains . Indeed, most IR missense or nonsense mutations located outside the TK domain are thought to incompletely impair IR activity, and most asymptomatic carriers who were discovered by familial studies of RMS and DS have INSR mutations outside the TK domain . The regional dependency of the residual activity would affect the penetrance of Type A IR due to heterozygous INSR mutation.…”

“…To evaluate the effect of insulin signaling defects during the fetal period, we compared the SDSs of birth weight between patients with Donohue syndrome (DS), Rabson–Mendenhall syndrome (RMS), and Type A IR. In addition to the present cases, we collected perinatal information for 12 Japanese patients (five with Type A IR and seven with DS or RMS) and 28 patients from other countries (two with Type A IR, 15 with DS, and 11 with RMS) based on previous studies . All birth weight SDSs for all nine patients with Type A IR were < 0 (mean [±SD] –1.65 ± 0.85; range from −0.72 to −3.28).…”

“…Birth weight SDSs were calculated based on Japanese standards . (b) Birth weight SDS of the reported 40 patients with genetically proven severe IR . A, Type A IR; R, Rabson–Mendenhall syndrome; D, Donohue syndrome.…”

“…To assess correlations between phenotype severity and birth weight, perinatal information was collected for patients with genetically proven SIR from previous reports . Birth weight SDSs were calculated based on a Japanese reference and international standard .…”

“…To assess correlations between phenotype severity and birth weight, perinatal information was collected for patients with genetically proven SIR from previous reports. 3,4,[7][8][9][10][11][12][13][14][15][16][17][18][19][20] Birth weight SDSs were calculated based on a Japanese reference 21 and international standard. 22 For comparisons between groups, the significance of differences was evaluated using a Mann-Whitney U-test and one-way analysis of variance (ANOVA) followed by a Tukey-Kramer post test.…”