ABSTRACT
OBJECTIVE: We report a novel GLI2 frameshift mutation and describe the phenotypic spectrum of mutations within this gene. PATIENTS AND METHODS: A male with congenital hypopituitarism and polymalformation syndrome was clinically, biochemically and neuroradiologically characterized. Genetic analysis for congenital hypopituitarism was performed using a targeted NGS custom gene panel. RESULTS: A heterozygous frameshift mutation, NM_005270.4:c.2125del, p.(Leu709Trpfs*15), was identified in GLI2 exon 12. This mutation has not been previously reported and confirms the diagnosis of Culler-Jones syndrome (MIM #615849). CONCLUSION: GLI2 mutations should be suspected in the presence of congenital hypopitutarism, characteristic facial abnormalities and polydactyly.
Subject(s)
Abnormalities, Multiple/genetics , Cleft Palate/genetics , Frameshift Mutation , Hypopituitarism/congenital , Hypopituitarism/genetics , Nuclear Proteins/genetics , Zinc Finger Protein Gli2/genetics , Abnormalities, Multiple/pathology , Cleft Palate/pathology , Humans , Hypopituitarism/pathology , Infant, Newborn , Male , Phenotype , Prognosis , SyndromeABSTRACT
CONTEXT: Autosomal-recessive mutations in the growth hormone receptor (GHR) are the most common causes for primary growth hormone insensitivity (GHI) syndrome with classical GHI phenotypically characterized by severe short stature and marked insulin-like growth factor (IGF)-I deficiency. We report three families with dominant-negative heterozygous mutations in the intracellular domain of the GHR causing a nonclassical GHI phenotype. OBJECTIVE: To determine if the identified GHR heterozygous variants exert potential dominant-negative effects and are the cause for the GHI phenotype in our patients. RESULTS: All three mutations (c.964dupG, c.920_921insTCTCAAAGATTACA, and c.945+2T>C) are predicted to result in frameshift and early protein termination. In vitro functional analysis of variants c.964dupG and c.920_921insTCTCAAAGATTACA (c.920_921ins14) suggests that these variants are expressed as truncated proteins and, when coexpressed with wild-type GHR, mimicking the heterozygous state in our patients, exert dominant-negative effects. Additionally, we provide evidence that a combination therapy of recombinant human growth hormone (rhGH) and rhIGF-I improved linear growth to within normal range for one of our previously reported patients with a characterized, dominant-negative GHR (c.899dupC) mutation. CONCLUSION: Dominant-negative GHR mutations are causal of the mild GHI with substantial growth failure observed in our patients. Heterozygous defects in the intracellular domain of GHR should, therefore, be considered in cases of idiopathic short stature and IGF-I deficiency. Combination therapy of rhGH and rhIGF-I improved growth in one of our patients.
Subject(s)
Chromosomes, Human, Pair 13/genetics , Chromosomes, Human, Pair 20/genetics , Genetic Association Studies , Monosomy/genetics , Trisomy/genetics , Adult , Child , Child, Preschool , Chromosome Banding , Chromosome Deletion , Comparative Genomic Hybridization , Female , Humans , Infant , Infant, Newborn , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , PregnancyABSTRACT
Orofaciodigital syndromes have many clinical and cephalometric anomalies, including facial irregularities, oral cavity abnormalities, and malformations of fingers and toes. In this case of twin girls, buccal exploration, cephalometric examination, and genetic analysis were performed to diagnose Orofaciodigital I or Orofaciodigital II syndrome. Clinically, the twins had several dental and skeletal irregularities. Genetic analysis revealed a DNA segment abnormality corresponding to exon 3 and presence of nucleotide change, 243C>G, leading to the missense mutation H81Q. This causative mutation associated with the OFD1 gene has not been reported previously. Both patients were diagnosed as having Orofaciodigital I syndrome.
