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1.
J Clin Endocrinol Metab ; 104(7): 2925-2930, 2019 07 01.
Article in English | MEDLINE | ID: mdl-30811539

ABSTRACT

CONTEXT: The transcription factor RAX is a paired-type homeoprotein that plays a critical role in eye and forebrain development of vertebrate species. RAX knockout mice have anophthalmia, cleft palate, and an abnormal hypothalamus and display perinatal lethality. In humans, homozygous or compound heterozygous RAX mutations have been reported to cause bilateral microphthalmia or anophthalmia without consistent associated features. Congenital hypopituitarism can be associated with various eye or craniofacial anomalies; however, the co-occurrence of congenital hypopituitarism, anophthalmia, cleft palate, and diabetes insipidus has been very rare. RESULTS: We report the case of a child with anophthalmia, congenital hypopituitarism, diabetes insipidus, and bilateral cleft lip and palate who had a homozygous frameshift truncating mutation c.266delC (p.Pro89Argfs*114) in exon 1 of the RAX gene. Rax knockout mice show loss of ventral forebrain structures, pituitary, and basosphenoid bone and palate and a misplaced anterior pituitary gland along the roof of the oral cavity. CONCLUSIONS: Our patient's phenotype was more severe than that reported in other patients. Although most of the previously reported patients with RAX mutations showed either a missense or some less severe mutation in at least one of their RAX alleles, our patient was homozygous for truncating mutations that would yield a severe, null protein phenotype. The severity of the genetic defect, the precise match between the knockout mouse and the patient's endocrine phenotypes, and the prominent roles of RAX in eye and pituitary development and diencephalic patterning suggest that the RAX null mutations could fully account for the observed phenotype.


Subject(s)
Anophthalmos/genetics , Cleft Lip/genetics , Cleft Palate/genetics , Diabetes Insipidus/genetics , Eye Proteins/genetics , Homeodomain Proteins/genetics , Hypopituitarism/genetics , Transcription Factors/genetics , Animals , Anophthalmos/diagnostic imaging , Anophthalmos/pathology , Antidiuretic Agents/therapeutic use , Cleft Lip/diagnostic imaging , Cleft Lip/pathology , Cleft Palate/diagnostic imaging , Cleft Palate/pathology , Deamino Arginine Vasopressin/therapeutic use , Diabetes Insipidus/diagnostic imaging , Diabetes Insipidus/drug therapy , Diabetes Insipidus/pathology , Frameshift Mutation , Hormone Replacement Therapy , Human Growth Hormone/therapeutic use , Humans , Hydrocortisone/therapeutic use , Hypopituitarism/diagnostic imaging , Hypopituitarism/drug therapy , Hypopituitarism/pathology , Infant, Newborn , Magnetic Resonance Imaging , Male , Melatonin , Mice, Knockout , Pituitary Gland/abnormalities , Thyroxine/therapeutic use
2.
Hum Mol Genet ; 13(3): 315-22, 2004 Feb 01.
Article in English | MEDLINE | ID: mdl-14662654

ABSTRACT

Anophthalmia and microphthalmia are among the most common ocular birth defects and a significant cause of congenital blindness. The etiology of anophthalmia and microphthalmia is diverse, with multiple genetic mutations associated with each of these conditions, along with potential environmental causes. Based on findings that mutations in the Rx/Rax homeobox genes in mice and fish lead to defects in retinal development and result in animal models of anophthalmia, we screened 75 individuals with anophthalmia and/or microphthalmia for mutations in the human RAX gene. We identified a single proband from this population who is a compound heterozygote for mutations in the RAX gene. This individual carries a truncated allele (Q147X) and a missense mutation (R192Q), both within the DNA-binding homeodomain of the RAX protein, and we have characterized the biochemical properties of these mutations in vitro. Parents and grandparents of the proband were found to be carriers without visible ocular defects, consistent with an autosomal recessive inheritance pattern. This is the first report of genetic mutations in the human RAX gene.


Subject(s)
Anophthalmos/genetics , Cornea/abnormalities , Eye Proteins/genetics , Homeodomain Proteins/genetics , Transcription Factors/genetics , Child, Preschool , Codon, Nonsense , Humans , Infant, Newborn , Male , Mutation, Missense , Orbit/abnormalities , Orbit/diagnostic imaging , Pedigree , Radiography
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