Disorganization, Mouse, Homolog Of

Donnai and Winter (1989) presented examples of 5 fetuses and 1 newborn with abnormalities difficult to explain on the basis of amniotic bands (see 217100) and suggested that these may result from a mutant gene, the homolog of the mouse mutant 'disorganization' (Ds). The mouse mutant is a semidominant with variable expression in heterozygotes and lethality in homozygotes (Hummel, 1959). Donnai and Winter (1989) reviewed the features of the mouse mutation including the high frequency of limb duplications, usually involving a single limb; polydactyly, sometimes of high degree and undifferentiated; and limbs originating from abnormal sites. Human cases of the same nature were collected from the literature and a new case was added. Winter and Donnai (1989), in reporting a patient with striking congenital defects including 9 toes on the right leg and a fingerlike structure arising from the abdomen, suggested that such cases may represent the human homolog of mice heterozygous for the single 'disorganisation' (Ds) semidominant gene. Lin (1991) presented another proposed example.

Petzel and Erickson (1991) suggested that the 'disorganisation' mutation is responsible for the findings in patients with duplications of internal organs and external structures of the lower half of the body that have traditionally been explained as incomplete twinning.

A statistical analysis suggested to Crosby et al. (1993) that occurrence of anomalies in mice with the Ds mutation follows a Poisson distribution. Their results further suggested that congenital anomalies in mice with this mutation occur independently of each other. Crosby et al. (1993) proposed that Ds causes a heritable predisposition to congenital anomalies and that Ds combined with appropriate somatic events compromises normal development. They also proposed that some sporadic, nonheritable congenital anomalies involve somatic mutations at Ds-like loci. They pictured some typical anomalies including polydactyly of the limb of the duplication type (135750, 188740). The parallelism to the Knudson hypothesis for cancer is obvious. In that case also, the statistical approach demonstrating a Poisson distribution for the number of tumors per eye for retinoblastoma (Knudson, 1971) or per kidney for Wilms tumor (Knudson and Strong (1972)) supported a random distribution for a second hit.

Lowry and Yong (1991) described 2 Chinese brothers with cleft lip/palate, profound sensorineural deafness, and a sacral lipoma. One had aberrant digital appendages on the heel and thigh, whereas the other had an anterior sacral meningocele and dislocated hip. Intelligence was normal in both. Both boys suffered from functional constipation, but biopsy studies showed no evidence of Hirschsprung disease. The parents were normal and unrelated. Lowry and Yong (1991) suggested that this mutation might be homologous to 'disorganisation,' located on chromosome 14 of the mouse (Hummel (1958, 1959)).

Robin et al. (1993) reported 2 unrelated patients with malformations similar to those in mice with the Ds mutation. The first case had a body wall defect, limb malformations and hamartoma, while the second case had a partially duplicated foot, as well as other anomalies. They discussed the findings in relation to the 2-hit hypothesis of Crosby et al. (1993): that there is a heritable predisposition and that a 'second hit,' either somatic mutation or an epigenetic event, determines the type of malformation. They considered the hypothesis attractive because it explained both the low penetrance and the variable expression of the Ds mutation.

Woods et al. (1995) described a male infant with a partial foot with 2 toes arising from the right buttock, hypoplasia of the right leg and right foot, absence of the right kidney, and severe hypoplasia of the right common iliac artery. The infant's karyotype was 47,XXY. Woods et al. (1995) discussed a possible role of arterial hypoplasia in the origin of limb underdevelopment.

Onal et al. (2005) reported a newborn infant with defects similar to those seen in mice heterozygous for the mutant Ds gene. The child had left popliteal webbing, left iliac bone hypoplasia, bifid scrotum, hypospadias, chordee deformity of the penis, and a sacral dimple. Other anomalies included absence of the right kidney and a hamartomatous tubular skin pedicle on the left thigh. No obvious amniotic bands or oligohydramnios were noted. The similarity between the proband's anomalies, those in previously reported cases, and those found in mice supported the possibility of a human homolog of the Ds gene.

Isidor et al. (2009) reported 6 patients with congenital pedicle skin hamartomatous lesions. Two patients showed a single skin pedicle lesion; 1 of these was shown to have 22q11.2 deletion, and 4 patients had, in addition to the single skin pedicle, severe limb anomalies for which they were originally diagnosed with amniotic band sequence (217100). Isidor et al. (2009) proposed that all of these infants instead showed various forms of a phenotype resembling Ds in the mouse and suggested that this phenotype may be associated with apparent amniotic band syndrome. They proposed calling this 'amniotic band syndrome plus.' All patients were the children of nonconsanguineous parents. Patient 1 of Isidor et al. (2009) had multiple anomalies including limb defects, constriction rings, partial syndactyly, and a pedicle skin lesion on the occipital region. The skin pedicle was removed at 12 months of age and showed a tuberous hamartomatous lesion. Patient 2 had multiple anomalies including limb defects and a pedicle skin lesion on the vertex; a pedicular skin lesion on the vertex had also been present in the maternal grandfather and great-grandfather. Constriction rings were present on the proximal phalanx of the second, third, and fourth digits of the left hand, with distal amputation of the last phalanx of the index finger. Lower limbs were normal except for equinovarus feet. Patient 3 had multiple limb anomalies, constriction rings, and a pedicle skin lesion on the back. A pedicular skin lesion was also present at the external side of the right ankle with a hemicircumferential constriction ring. Patient 4 had a right cleft lip, detected by ultrasound at 20 weeks' gestation, as well as limb defects, constriction rings, partial syndactyly, and a pedicle skin lesion on the head. Patient 5 had a lumbar fingerlike pedicle and bifid uvula. Spinal cord MRI was normal apart from this pedicle skin lesion at the level of L2-L3 which seemed to be linked to L4 by a fibrous tract. At 6 years of age, nasal speech and speech delay were noted. Physical exam showed small round ears, small mouth, and iris heterochromia. Brain MRI showed frontal polymicrogyria. Chromosome and FISH analyses were performed and showed a 46,XX karyotype with 22q11.2 microdeletion. Patient 6 had a dorsal fingerlike pedicle. Examination was otherwise normal apart from a single palmar crease on the left hand. Axial skeleton x-ray showed 11 pairs of ribs. MRI showed absence of fusion of the posterior arch of S1. Except for the patient with 22q11.2 microdeletion, neurologic examination and psychomotor development was normal.

Purandare et al. (2009) reported 4 patients with developmental anomalies seen in amniotic band sequence, with additional anomalies that could not be explained by amniotic bands alone. The anomalies seen in their patients included facial malformation and clefting, brain anomalies (encephalocele, agenesis of the corpus callosum, holoprosencephaly), eye anomalies (anophthalmia, microphthalmia, and microcornea), and extremity and digit anomalies (talipes equinovarus, syndactyly). Other phenotypic features included genitourinary anomalies (hydronephrosis and abnormal testes, epididymis, and seminal vesicles) and skin appendages similar to those seen in Ds mice. Presence of amniotic bands in addition to malformations not attributed to amniotic bands were seen in 3 of 4 patients. Purandare et al. (2009) concluded that the 4 patients in their report had involvement of at least 4 organ systems, including the skin appendages, that had been reported in the Ds mouse, and had clinical findings that overlap the spectrum of Ds and amniotic band sequence. Patient 1 had anterior encephalocele, hypertelorism, Tessier 4-5 facial cleft, bilateral microphthalmia, and microcornea, rudimentary nose, talipes equinovarus, and skin appendages/hamartomas near the right eye and over the right forearm. The patient expired on day 4 of life due to respiratory complications. Patient 2 had left superior facial disruption of the nose and midline facial structures by amniotic bands including severe clefting of the midline external soft tissues and bony structures. There was amputation of the left upper extremity at the level of the distal humerus. Various brain anomalies included frontal encephalocele, periventricular leukomalacia, and agenesis of the corpus callosum. This patient survived a few hours. Patient 3, who survived for 57 minutes, had a large omphalocele with amniotic bands attached to the umbilical cord. This band attached at the opposite end to the tip of a cutaneous polyp on the inner surface of the right upper arm. Cleft lip and palate, disruption of the nose, and disruption and displacement of the eyes with anophthalmia/microphthalmia was also seen. The base of the skull was abnormal and had a shallow sella turcica with absent pituitary. An ectopic pituitary was present in the nasopharyngeal submucosa. The karyotype of the fourth patient, delivered as spontaneous intrauterine fetal demise, showed mosaicism for trisomy 3. There were severe facial clefts involving palate, lip, nose, and right eyelid. There was a left-sided body wall defect from left pleural apex to sacral level and from midline to posterior body wall with absence of the left chest wall. The left upper extremity was attached near the dorsal pelvis.

Animal Model

Robin et al. (1997) gave an extensive review of the Ds mutation in mice, pointing out that the range of malformations is so great that no 2 affected mice are identical. Most affected mice have only a single malformation, and most of these malformations are similar to both common (neural tube defects, orofacial clefting, gastroschisis, limb reductions) and rare (anophthalmia, duplicated rectum) human birth defects. Robin et al. (1997) suggested that the low penetrance (under 30%) and highly variable expression of Ds make it a paradigm for understanding the genetic basis for many seemingly sporadic birth defects of humans.