deamino-arginine-vasopressin and Cleft-Palate

Topics: Abnormalities, Multiple; Administration, Intravenous; Administration, Oral; Cleft Lip; Cleft Palate; Deamino Arginine Vasopressin; Diabetes Insipidus, Neurogenic; Drug Administration Routes; Drug Compounding; Female; Gastrostomy; Holoprosencephaly; Humans; Infant; Infusions, Parenteral

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.. 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.. 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.

Topics: Animals; Anophthalmos; Antidiuretic Agents; Cleft Lip; Cleft Palate; Deamino Arginine Vasopressin; Diabetes Insipidus; Eye Proteins; Frameshift Mutation; Homeodomain Proteins; Hormone Replacement Therapy; Human Growth Hormone; Humans; Hydrocortisone; Hypopituitarism; Infant, Newborn; Magnetic Resonance Imaging; Male; Melatonin; Mice, Knockout; Pituitary Gland; Thyroxine; Transcription Factors

A 3-month-old child with bilateral cleft lip and palate and holoprosencephaly was hospitalized after he developed diabetes insipidus presumably due to hypothalamic dysfunction. He was initially treated with subcutaneous vasopressin injection but was switched to therapy with desmopressin acetate (DDAVP) before discharge. Because of his abnormal nasopharyngeal anatomy, we decided to administer the desmopressin acetate sublingually, and this was effective. A single daily dose of 2 micrograms (0.4 microgram/kg) resulted in a prompt antidiuresis, and the effect gradually lessened over a 24-hour period. Serum electrolyte values were restored to normal and have remained normal after three months of treatment. After additional study, the sublingual route might be considered for the administration of small-polypeptide therapeutic agents when other routes are impractical.

Topics: Abnormalities, Multiple; Adult; Brain; Cleft Lip; Cleft Palate; Deamino Arginine Vasopressin; Diabetes Insipidus; Drug Administration Routes; Female; Humans; Infant, Newborn; Male; Pregnancy