Gapo Syndrome

A number sign (#) is used with this entry because of evidence that GAPO syndrome (GAPOS) is caused by homozygous mutation in the ANTXR1 gene (606410) on chromosome 2p13.

Description

GAPO syndrome is the acronymic designation for a complex of growth retardation, alopecia, pseudoanodontia (failure of tooth eruption), and progressive optic atrophy (Tipton and Gorlin, 1984). Ilker et al. (1999) and Bayram et al. (2014) noted that optic atrophy is not a consistent feature of the disorder.

Clinical Features

Tipton and Gorlin (1984) reported a case and reviewed cases in the literature, including a follow-up on the first reported case. Because of the striking phenotype, diagnosis as early as 6 months should be possible in most cases. Frontal bossing, high forehead, midfacial hypoplasia and wide-open anterior fontanel suggest skeletal dysplasia. Bone age is retarded.

Gagliardi et al. (1984) reported 3 affected brothers with consanguineous parents. They found information on 9 cases (4 males, 5 females). One of the patients died at age 39 years and another at age 37 years. Manouvrier-Hanu et al. (1987) described the case of a 4-year-old Algerian girl born of first-cousin parents. The patient had cerebrovenous circulatory anomalies causing greatly dilated scalp veins. The authors pointed out that this is a progeroid syndrome.

Wajntal et al. (1990) stated that 12 patients with the GAPO syndrome, distributed in 7 families, had been reported. They added the clinical data related to affected brother and sister and the autopsy findings in the brother. Both had the characteristic features of the syndrome except that optic atrophy was absent; instead they had glaucoma and keratoconus. Hypogonadism was present in both sibs. Biopsy and autopsy findings suggested that the GAPO syndrome is a 'dyshistogenetic sequence' due to accumulation of extracellular material, leading Wajntal et al. (1990) to suggest that it should be called GAPO dysplasia. They suggested that there is a lack of breakdown of extracellular components, perhaps due to deficiency of an enzyme involved in the metabolism of extracellular matrix. The brother began to have recurrent eye, ear, and respiratory infections at the age of 34; he died at age 35 of bronchopneumonia and respiratory acidosis. The sister was born with normal black hair on the scalp but lost this progressively after age 1 year and had complete alopecia by age 2. Choanal stenosis caused respiratory problems. At the age of 20 she was about 120 cm tall. Her brother was about 135 cm at age 27.

Sayli and Gul (1993) described GAPO syndrome in a brother and sister and in a first cousin. Somewhat different features included the presence of some body hair, white eyelashes, deep furrows on the sternum and back, disproportionate body build, and minor skeletal abnormalities. The cousin had severe glaucoma and band keratopathy of one eye. The parents of the first cousin were related as first cousins. As young adults, the cousin and the brother were 143 and 144 cm tall, respectively.

Sandgren (1995) reported what he claimed was the fifteenth recognized case of GAPO syndrome. The patient, a 9-year-old girl, showed growth retardation, alopecia, and pseudoanodontia, but no signs of optic atrophy. Moriya et al. (1995) reported the first case in Japan, a 3.5-year-old boy with growth retardation, alopecia, pseudoanodontia, and bilateral papilledema. The child had permanent dilatation of scalp veins and an audible intracranial bruit. Cranial angiography documented a narrowing of the sigmoid sinuses, with no flow to either jugular vein.

Meguid et al. (1997) reported on a 3-year-old Egyptian boy with growth retardation, alopecia, pseudoanodontia, and optic atrophy. They stated that this was the eighteenth known and first Egyptian case of GAPO syndrome. Electron microscopic examination of gingival biopsy showed excessive collagen fibers and endothelial vacuolization, suggesting involvement of extracellular pathologic collagenosis.

Baxova et al. (1997) described 2 unrelated patients with GAPO syndrome, a 15-month-old Czech boy and a 16-month-old Polish girl. In addition, they published a photograph of a 5-year-old boy with apparent GAPO syndrome, whose features included short stature, alopecia and progeroid appearance, large ears, depressed nasal bridge, prominent cheeks, thin lips, large tongue, unerupted teeth, micrognathia, and large genitalia.

Bacon et al. (1999) reported a 29-year-old French man, born of distantly related parents, with short stature, dysmorphic craniofacial features, total alopecia, and pseudoanodontia. Erupted primary dentition was extremely worn and on radiographic examination, the second mandibular molars were found to be unerupted, together with the entire permanent dentition. Cephalometry revealed absence of facial pneumatization, a deficient cranial base with diminished upper face height, and maxillary and mandibular hypoplasia with a prognathic skeletal pattern. Histologic examination of an extracted primary incisor and its surrounding root bone revealed extensive ankylosis. Bacon et al. (1999) stated that this was the twenty-fourth published case of GAPO syndrome, and reviewed the relative importance of the various phenotypic features in diagnosis.

Goloni-Bertollo et al. (2008) described 2 sisters and a brother with GAPO syndrome, the offspring of first-degree cousin parents. All 3 sibs presented the characteristic phenotype but also had serious bone alterations in the lower limbs and cognitive defects. The bone alterations included enlargement of the metaphyses, shortening and the presence of a prominent arch of the long bone, a short square iliac and alteration of the thoracic and lumbar vertebrae and enlargement of the costal arches, bell-shaped chest, and enlargement of the proximal part of the clavicle. One of the sisters did not have optic atrophy. The brother also had a renal dysfunction.

Kocabay and Mert (2009) reported a 31-year-old man with GAPO syndrome who presented with dyspnea and was diagnosed with dilated cardiomyopathy (CMD; see 115200). Limited endocrinologic analysis revealed a normal GH (139250) level but a low IGF1 (147440) level. Kocabay and Mert (2009) stated that this was the first patient reported to have GAPO syndrome and CMD and suggested that the association might be due to dysfunction of the growth hormone axis.

Castrillon-Oberndorfer et al. (2010) reported an 11-year-old boy, born of first-cousin Turkish parents, who had psychomotor retardation, alopecia, optic atrophy, impacted upper and lower teeth, and the characteristic craniofacial dysmorphism of GAPO, including high and bossed forehead, midface hypoplasia, and retro- and micrognathia. In addition, the patient had a large craniofacial vascular malformation, originating in an occipital sponge-like formation with protrusions to the frontal, parietal, and temporal skull. Cerebral angiography using CT and MRI showed largely widened cortical veins, with a compressed or missing left transverse and sigmoid sinus and an undeveloped left jugular vein. The palpable spongy vascular mass on the outer skull showed a transosseous connection to the intracranial vessel system and was therefore believed to represent emissary veins. Castrillon-Oberndorfer et al. (2010) noted that of 33 GAPO patients reported, this was the fourth in whom a vascular malformation had been described.

Bayram et al. (2014) reported 5 affected individuals from 3 Turkish families with GAPO syndrome. Common findings included alopecia, relative macrocephaly, frontal bossing, low-set and protruding ears, hypertelorism, thickened eyelids, sparse eyebrows and eyelashes, depressed nasal bridge, long philtrum, thick lips, and micrognathia. Patients also had increased subcutaneous accumulations with age that produced coarsened facial features. Ophthalmic findings included keratopathy in 3 patients, myelinated retinal nerve fiber in 2 patients, and glaucoma in 4 patients. As previously noted by Ilker et al. (1999), optic atrophy was not consistently seen. One of the patients died at age 37 due to central apnea and respiratory insufficiency.

Inheritance

Parental consanguinity and the occurrence of affected sibs suggest autosomal recessive inheritance of GAPO syndrome (Tipton and Gorlin, 1984).

Molecular Genetics

In a Czech family with GAPO syndrome, previously reported by Baxova et al. (1997), Stranecky et al. (2013) performed exome sequencing and identified only 1 variant compatible with a recessive disorder, a homozygous nonsense mutation in the ANTXR1 gene (R169X; 606410.0002). Analysis of the ANTXR1 gene in 3 additional GAPO probands, including the Egyptian patient reported by Meguid et al. (1997), an unrelated Egyptian patient, and a Sri Lankan patient, revealed homozygosity for another nonsense mutation (R88X; 606410.0003) in the 2 Egyptian patients and a splice site mutation in the Sri Lankan (606410.0004). Phalloidin staining demonstrated a striking reorganization of actin cytoskeletal microfilaments in GAPO fibroblasts, suggesting that ANTXR1 is crucial for actin assembly and that disruption of the actin network might be the major pathogenetic event leading to altered cell adhesion properties and progressive extracellular matrix build-up observed in individuals with GAPO syndrome.

In 5 affected individuals from 3 Turkish families with GAPO syndrome, Bayram et al. (2014) identified 3 novel homozygous mutations in the ANTXR1 gene (606410.0005-606410.0007). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were predicted to produce an abnormal gene product. None of the mutations were reported in the 1000 Genomes Project, NHLBI Exome Sequencing Project, or dbSNP databases, or in an internal database of over 2,600 exomes. A search of the internal exome database found heterozygous ANTXR1 missense variants in 4/465 (0.86%) members of the Turkish population; a search of an international multiethnic comparison database found heterozygous missense variants in ANTXR1 in 42/5,748 (0.73%) Europeans and in 84/2,854 (2.9%) African Americans.