Aminopterin Syndrome Sine Aminopterin
Description
The pseudoaminopterin syndrome (aminopterin syndrome sine aminopterin; ASSA) is a multiple congenital anomaly disorder characterized by ossification defects of the skull, dysmorphic facial features, delayed development, and variable limb defects. The clinical features resemble the embryopathy caused by maternal treatment with the folic acid antagonist aminopterin, which has been recognized since 1952 (Thiersch, 1952) when aminopterin was used as an abortifacient. The characteristic phenotype of the children who survived infancy after having been exposed to aminopterin or its methyl derivative, methotrexate, in early pregnancy included a very unusual facies, skull anomalies, and skeletal defects (summary by Fraser et al., 1987).
Clinical FeaturesHerrmann and Opitz (1969) described 'an unusual form of acrocephalosyndactyly' that resembled the phenotype of the syndrome produced by aminopterin in early pregnancy. The patient presented with turribrachycephaly, hypertelorism, blepharophimosis, craniolacunae, syndactyly, and mental retardation. A similar case was later described by Reich et al. (1978), but the patient did not have mental retardation. Chen et al. (1990) suggested that the ASSA syndrome was present in the patient reported by Herrmann and Opitz (1969) and in the patient reported by Reich et al. (1978).
Fraser et al. (1987) described 2 unrelated children with multiple malformations characteristic of the aminopterin syndrome, but without any evidence of exposure to aminopterin in the mothers. The first patient, a girl, had hydrocephaly, cleft lip/palate, and dysmorphic features, including hypertelorism, facial asymmetry, dolichocephaly, frontal bossing, unusual hair pattern, and hypoplastic right thumb. She had delayed development, short stature, and seizures. Examination at age 7 years showed upsweep of the eyebrows, small irregularly placed teeth, low-set, posteriorly rotated ears with absent lobes, inverted and widely spaced nipples, clubbing of the nails, and inturned right foot. She had synostosis of the sagittal suture and mild conductive hearing loss. The second child was a 9-year-old black boy with short stature, thin habitus, and delayed development. He had a small head, shallow supraorbital ridges, hypertelorism, short palpebral fissures, high-arched eyebrows, upswept hairline, low-set and posteriorly rotated ears, micrognathia, and open sagittal suture. He also had high myopia, incomplete ophthalomoplegia, and mild motor weakness. Other features included cryptorchidism and flexion contractures. Radiographs showed ossification defects of the cranial vault, both dense and unossified, unusual iliac wings, and thin long bones. Fraser et al. (1987) suggested that this constellation of findings represented a new syndrome, which could be called the aminopterin-like syndrome sine aminopterin (ASSA) syndrome. Fraser et al. (1987) suggested that the disorder reported in 3 sibs as a new syndrome by Crane and Heise (1981) may also be the ASSA syndrome; see 218090.
Krajewska-Walasek (1994) reported affected sibs. The first-born affected child, a girl, was delivered at 36 weeks' gestation with a weight at the 3rd percentile and a head circumference greater than the 97th percentile. The second affected, a boy, also had head size at the 97th percentile at birth. Both had an unusual appearance, were hypotonic, and had rudimentary postaxial polydactyly of the hands and an umbilical hernia. The boy, in addition to ossification defects in the frontal and parietal bones, had an inguinal hernia. The phenotype changed with age. The male had the more striking skeletal features: long and slender fingers with marked camptodactyly of some of them, severe thoracic scoliosis, and abnormalities of the feet which remained in valgus position. Krajewska-Walasek (1994) pointed to the phenotypic confusion with the Juberg-Hayward syndrome (216100).
Barnicoat et al. (1994) described a male fetus with multiple congenital abnormalities and consanguineous parents. There were unusual facial features, digital anomalies, cleft palate, a malformed tongue that prevented swallowing, absent clavicles, and genital hypoplasia. Barnicoat et al. (1994) noted that these features suggest both Crane-Heise syndrome and aminopterin syndrome sine aminopterin, and may represent part of a spectrum of abnormalities including these 2 conditions.
Sobreira et al. (2009) reported a 9-year-old girl, born to unaffected consanguineous parents, with short stature, microcephaly, broad forehead with high hair implantation, sparse and fine hair with areas of alopecia, arched eyebrows, synophrys, hypertelorism, epicanthal folds, palpebral ptosis, oligodontia, low-set and small ears with hypoplasia of antihelices. Skeletal anomalies included brachydactyly, clinodactyly, hypoplasia of the 4th metacarpal, clinodactyly of the 4th and 5th toes, overlapping toes and bilateral hip luxation. She also had patent foramen ovale, left posterior diaphragmatic hernia, absence of spleen, and horseshoe kidney. She had delayed early motor development, but finished second grade with normal performance. She also had normal ossification of the skull. She, her unaffected mother, and unaffected brother had an inv(9)(p12q13) polymorphism. Although this patient had some characteristics not described before in patients with ASSA, such as ptosis, left posterior diaphragmatic hernia, absence of spleen, and horseshoe kidney, her phenotype was most strongly reminiscent of the pseudoaminopterin syndrome.
InheritanceKrajewska-Walasek (1994) reported the first familial cases. Abnormalities in a brother and sister supported autosomal recessive inheritance, although parental consanguinity was excluded.
CytogeneticsChen et al. (1990) observed the ASSA syndrome in association with a mosaic translocation t(5;10)(q35;q22). They suggested that pseudoaminopterin syndrome would be an appropriate designation.