What are the other Names for this Condition? (Also known as/Synonyms)

• Growth Retardation, Alopecia, Pseudoanodontia and Optic Atrophy Syndrome

What is GAPO Syndrome? (Definition/Background Information)

• GAPO Syndrome is a multiple congenital anomalies (MCA) syndrome involving connective tissue, characterized by Growth retardation, Alopecia, Pseudoanodontia and Ocular manifestations. Approximately 38 patients have been reported in literature since the first description in 1947
• Patients have a short stature due to post-natal growth retardation and typical facies with high and bossing forehead, hypertelorism, puffy eyelids, midfacial hypoplasia, depressed nasal bridge, anteverted wide nostrils, thick everted lower lip, micrognathia, low-set 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 leading to complete or partial alopecia. Eyebrows and/or eyelashes are sparse. Primary and permanent teeth are formed but fail to erupt
• Ocular manifestations may include progressive optic atrophy, glaucoma, strabismus, megalocornea, myelinated retinal nerve fiber layer, bilateral keratoconus, nystagmus and ptosis
• Otorhinolaryngologic 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, hepatomegaly, renal impairment and altered gonadal functions (irregular periods or amenorrhea, oligoastenospermia)
• Antenatal diagnosis is not possible as features are not detectable by fetal ultrasound. GAPO Syndrome appears to have an autosomal recessive transmission pattern
• There is no curative treatment. Management mostly relies on ophthalmologic surveillance and symptomatic treatment of the multiple health problems

(Source: GAPO Syndrome; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Who gets GAPO Syndrome? (Age and Sex Distribution)

• GAPO Syndrome is a rare congenital disorder with less than 40 cases reported to date
• The presentation of symptoms may occur at birth
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for GAPO Syndrome? (Predisposing Factors)

• A positive family history may be an important risk factor, since GAPO Syndrome can be inherited
• Currently, no other risk factors have been clearly identified for the syndrome

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of GAPO Syndrome? (Etiology)

• Homozygous nonsense or splicing mutations in the ANTXR1 gene, encoding anthrax toxin receptor 1, also known as tumor endothelial marker 8 (TEM8) cause GAPO Syndrome
• It appears to have an autosomal recessive transmission pattern

(Source: GAPO Syndrome; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of GAPO Syndrome?

The signs and symptoms of GAPO Syndrome may include:

• Abnormality of metabolism/homeostasis
• Breast hypoplasia
• Delayed cranial suture closure
• Growth delay
• Hypoplastic nipples
• Hypotrichosis
• Prominent scalp veins
• Protruding ear
• Thick lower lip vermilion
• Tubulointerstitial fibrosis
• Unerupted tooth
• Wide anterior fontanel

Very frequently present symptoms in 80-99% of the cases:

• Alopecia
• Anteverted nares
• Broad forehead
• Delayed eruption of teeth
• Delayed skeletal maturation
• Early balding
• Everted lower lip vermilion
• Frontal bossing
• High forehead
• Hyperextensible skin
• Hypertelorism
• Joint hyperflexibility
• Long philtrum
• Low-set ears
• Micrognathia
• Midface retrusion
• Palpebral edema
• Prematurely aged appearance
• Sparse and thin eyebrow
• Sparse eyelashes
• Thick nasal alae
• Underdeveloped supraorbital ridges

Frequently present symptoms in 30-79% of the cases:

• Abnormal form of the vertebral bodies
• Abnormality of pelvic girdle bone morphology
• Abnormality of the cerebral vasculature
• Abnormality of the clavicle
• Abnormality of the metaphysis
• Abnormality of the palate
• Glaucoma
• Keratoconus
• Skin tags
• Umbilical hernia
• Visual impairment

Occasionally present symptoms in 5-29% of the cases:

• Amenorrhea
• Asymmetry of the thorax
• Atherosclerosis
• Choanal atresia
• Decreased skull ossification
• Dysmenorrhea
• Hearing impairment
• Hemangioma
• Hypogonadism
• Hypopigmented skin patches
• Increased intracranial pressure
• Myopia
• Nephrolithiasis
• Nystagmus
• Oligospermia
• Optic atrophy

(Source: GAPO Syndrome; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How is GAPO Syndrome Diagnosed?

• The diagnosis of GAPO Syndrome mostly relies on physical examination
• Cerebral angiography and magnetic resonance angiography reveal prominent cortical veins, occluded or absent left transverse sinus, left sigmoid sinus, agenesis of left jugular vein, and enlarged veins underlying the palpable scalp masses
• Skin biopsy may reveal dermis anomalies including amorphous hyaline substance and recently reported pyoderma vegetans

(Source: GAPO Syndrome; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

What are the possible Complications of GAPO Syndrome?

The complications of GAPO Syndrome may include:

• Emotional stress due to cosmetic concerns
• Presence of multiple abnormalities affecting many organs
• Vision and hearing loss

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is GAPO Syndrome Treated?

• There is no curative treatment for GAPO Syndrome
• Management mostly relies on ophthalmologic surveillance and symptomatic treatment of the multiple health problems

(Source: GAPO Syndrome; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

How can GAPO Syndrome be Prevented?

Currently, GAPO Syndrome may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of GAPO Syndrome? (Outcomes/Resolutions)

• GAPO Syndrome patients are reported to have a reduced lifespan (until their 4th-6th decade of life)

(Source: GAPO Syndrome; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Additional and Relevant Useful Information for GAPO Syndrome:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/