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A rare, genetic, multiple congenital anomalies syndrome characterized by growth retardation, alopecia, pseudoanodontia and ocular manifestations.
ORPHA:2067Classification level: Disorder
Approximately 60 patients with GAPO syndrome have been reported in literature since the first description in 1947.
Patients have a short stature, growth retardation and a typical facies with high and bossing forehead, hypertelorism, puffy eyelids, midfacial hypoplasia, depressed nasal bridge, anteverted wide nostrils, thick and everted lower lip, micrognathia, protruding, low-set and folded ears, and premature aging appearance mainly due to redundant hyperelastic skin with unusual wrinkles. Scalp hair may be primarily present but disappears after the first months of life resulting in complete or partial alopecia. Eyebrows and/or eyelashes are sparse or in some cases absent. Primary and permanent teeth are formed but fail to erupt. Ocular manifestations may include progressive optic atrophy, glaucoma, strabismus, photophobia, megalocornea, myelinated retinal nerve fiber layer, bilateral keratoconus, nystagmus and ptosis. Otorhinolaryngological features are choanal atresia, deafness and presence of flaccid and pulsatile masses with an audible murmur in the mastoid area associated with dilated and tortuous scalp veins. Patients have a mild intellectual deficit. Some patients have also been reported with umbilical hernia, hyperextensible joints, osseous anomalies (congenital dislocation of hips or delayed bone age) and cutaneous manifestations (hemangioma or depigmented areas). Other manifestations include intracranial hypertension in infancy, hypothyroidism, mitral valve dysfunction or cardiomyopathy, pulmonary diseases, headache, hepatomegaly, renal impairment and altered gonadal functions (irregular periods or amenorrhea, oligoasthenospermia). Cryptorchidism, ankyloglossia and hearing loss is also reported.
Homozygous nonsense or splicing mutations in the ANTXR1 gene (2p13.3), encoding anthrax toxin receptor 1, also known as tumor endothelial marker 8 (TEM8) causes GAPO Syndrome.
Diagnosis mostly relies on physical and ophtamologic examination. Additionally skin biopsy, cerebral angiography and magnetic resonance imaging contribute to more specific diagnosis.
The differential diagnosis includes cerebral alterations and cutaneous manifestations such as prominent cortical veins, occluded or absent left transverse sinus and left sigmoid sinus, agenesis of left jugular vein, prominent scalp veins, dermis anomalies including amorphous hyaline substance, and pyoderma vegetans.
Prenatal diagnosis is not possible from fetal ultrasound (US). In utero growth retardation may be observed on US but is not specific.
The pattern of inheritance is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of that the risk of having an affected child at each pregnancy is 25%.
Management and treatment
There is no curative treatment. Management mostly relies on ophthalmologic surveillance and symptomatic treatment of the multiple health problems.
GAPO patients are reported to have a reduced lifespan (until the fourth to sixth decade of life).
A summary on this disease is available in Español (2020) Français (2020) Nederlands (2020) Deutsch (2003) Italiano (2003)