Blepharophimosis-intellectual deficit syndrome
-Rare developmental defect during embryogenesis
-Rare genetic disease
-Rare neurologic disease
Partial deletion of the short arm of chromosome 3
-Rare developmental defect during embryogenesis
-Rare genetic disease
Characteristic features of the distal 3p- syndrome include low birth weight, microcephaly, trigonocephaly, hypotonia, psychomotor and growth retardation, ptosis, telecanthus, downslanting palpebral fissures, and micrognathia. Postaxial polydactyly, renal anomalies, cleft palate, congenital heart defects (especially atrioventricular septal defects), ... Characteristic features of the distal 3p- syndrome include low birth weight, microcephaly, trigonocephaly, hypotonia, psychomotor and growth retardation, ptosis, telecanthus, downslanting palpebral fissures, and micrognathia. Postaxial polydactyly, renal anomalies, cleft palate, congenital heart defects (especially atrioventricular septal defects), preauricular pits, sacral dimple, and gastrointestinal anomalies are variable features. Although intellectual deficits are almost invariably associated with cytogenetically visible 3p deletions, rare patients with a 3p26-p25 deletion and normal intelligence or only mild abnormalities have been described (summary by Shuib et al., 2009).
Verjaal and De Nef (1978) reported a male infant with failure to thrive who had an asymmetric skull flattened on the left posterior side, triangular facies, low anterior hairline, ptosis, epicanthic folds, malformed ears with bilateral indentation of ... Verjaal and De Nef (1978) reported a male infant with failure to thrive who had an asymmetric skull flattened on the left posterior side, triangular facies, low anterior hairline, ptosis, epicanthic folds, malformed ears with bilateral indentation of lobules and a pit in the right anterior helix, downturned mouth with thin lips, high-arched palate, arched eyebrows, prominent nose with fleshy tip, micrognathia, and retrognathia. He had poorly developed external genitalia, with small penis and hypoplastic scrotum, and undescended testicles were palpable in the inguinal canals. Muscle hypoplasia of both upper arms was striking, and on both hands, the second finger was curved over the third, with the fifth finger curved inwardly over the fourth finger. He had rocker bottom feet, with a supplementary toe laterally on each foot and partial syndactyly of the second and third toes, and the right fifth toe was larger than the fourth. Over time, severe mental and physical retardation became evident, and hearing and sight were defective, although no anatomic or structural lesion was seen on ophthalmoscopic examination. G-banded chromosome analysis revealed a de novo heterozygous deletion of the short arm of chromosome 3: 46,XY,del(3)(p25). Verjaal and De Nef (1978) stated that this was the first report of monosomy 3p25. Schwyzer et al. (1987) described a 13-month-old girl with growth and developmental retardation who had terminal deletion of the short arm of chromosome 3, with a breakpoint at 3p25. Features present in the patient that were characteristic of the 3p- syndrome included low birth weight, microcephaly, brachy-trigonocephaly, high and narrow forehead with a prominent metopic suture, epicanthic folds, upslanting palpebral fissures, ptosis, depressed nasal bridge, anteverted nares, and small mandible. She had an anteriorly placed anus, but lacked the postaxial polydactyly that had been observed in about half of patients with 3p- reported at that time. Ophthalmoscopic evaluation at age 9 months revealed a prominent and possibly edematous optic disc and a poorly differentiated macula with absence of central and wall reflexes; electroretinography (ERG) was normal. Reviewing the findings in 13 previously reported patients, Schwyzer et al. (1987) emphasized that it was a pattern, rather than 1 or a few specific dysmorphisms and malformations, that was characteristic of terminal 3p deletion. A feature that appeared to be underreported was trigonocephaly, which was specifically mentioned in only 1 report but, Schwyzer et al. (1987) noted, was evident in published photographs of at least 4 other patients. Ramer et al. (1989) reported an unrelated female and male infant with identical deletions of the terminal portion of chromosome 3p, involving 3pter-p25. The female infant was small at birth and had periorbital edema, edema of hands and feet, and bilateral postaxial polydactyly. Examination at 5 months of age while hospitalized for growth failure and developmental delay revealed craniofacial manifestations, including scalp hypotrichosis, low posterior hairline, brachycephaly, midface hypoplasia, upslanting palpebral fissures with telecanthus, flat nasal bridge with a short upturned nose, simple philtrum with thin upper lip, micrognathia, and small cupped ears. Hands were small with bilateral simian crease and clinodactyly of the fifth fingers. Feet had a 'rocker bottom' configuration and incurving of the fourth and fifth toes. She had hypotonia in the upper limbs with hyperreactive deep tendon reflexes. On barium studies, she was found to have malrotation of the colon which was surgically corrected. Renal ultrasound showed abnormal positioning of the kidneys, mimicking 'horseshoe' kidney without a connecting isthmus. Audiometry was suggestive of moderate bilateral sensorineural hearing loss. Ophthalmologic examination demonstrated blepharophimosis, telecanthus, and possible nanophthalmos in addition to ptosis. Heart and brain were structurally normal by echocardiography and CT scan, respectively. The male patient was small, with weight, length, and occipital-frontal circumference all 2.5 SD below the mean at 13 months of age. He had low-set ears with posterior angulation and folded helices, long philtrum with thin upper lip, highly arched palate, and micrognathia. Evaluation of a heart murmur by electrocardiography revealed a complete endocardial cushion defect. Cranial ultrasound was normal. Chromosome analysis revealed an identical deletion of the terminal portion of chromosome 3p in each: p25[del(3)(p25pter)]. Ramer et al. (1989) reviewed 10 previously reported patients with deletion of bands p25pter and noted that they had a high frequency of growth failure, severe developmental retardation, and serious structural heart defects; the most frequently documented craniofacial anomalies included ptosis, synophrys, hypertelorism, thin upper lip, micrognathia, malformed or apparently low-set ears, and triangular face. Narahara et al. (1990) studied 2 unrelated female infants with monosomy for the distal portion of chromosome 3p. One patient, with a 46,XX,del(3)(p25.3) karyotype, showed the characteristic clinical manifestations of the 3p- syndrome, including growth failure, mental retardation, microcephaly with a flat occiput, triangular face, synophrys, blepharoptosis, hypertelorism, broad and flat nose, long philtrum, downturned mouth, micrognathia, apparently low-set and malformed ears, finger abnormalities, and deafness. The other patient, who had a 46,XX,r(3)(p26.1q29) karyotype, had a nonspecific phenotype with mental retardation, growth failure, and microcephaly. Narahara et al. (1990) reviewed 16 previously reported cases with deficiency of distal 3p and suggested that deficiency of the 3p25.3 band was critical to produce the main clinical manifestations of the del(3p) syndrome. Nienhaus et al. (1992) described a male infant with monosomy for distal 3p, involving deletion of 3pter-p25. At birth he was noted to have an unusual craniofacial appearance, with midface hypoplasia, flat nasal bridge with upturned nostrils, hypertelorism, ptosis, bilateral epicanthus, and periorbital edema; his mouth was downturned with thin lips, long philtrum, high-arched palate, and slight micrognathia, and he had low-set and malformed ears. In contrast to previously described cases, there was no microcephaly, the occiput was prominent, and he had unusually wide cranial sutures. In addition, he had postaxial hexadactyly of all limbs. Cardiac catheterization confirmed a congenital heart defect, consisting of atrial septal defect, ventricular septal defect, and patent ductus arteriosus, He had a small penis, hypospadias, and a skin dimple over the sacrum. The infant died of heart failure due to his serious congenital heart defect at 4 weeks of age. Review of 14 previously reported cases of 3p- syndrome showed the most frequent features (occurring in at least 10 of 15 patients) to be microcephaly, blepharoptosis, epicanthal folds, flat nasal bridge with upturned nostrils, long philtrum, and polydactyly. Mowrey et al. (1993) studied a male infant who had a terminal deletion of 3p that encompassed all of 3p26 and most or all of 3p25. The infant had low birth weight and length, and the newborn period was complicated by pneumonia and apneic episodes. Examination revealed microcephaly, flattened nasal bridge, hypertelorism, blepharophimosis, narrow palpebral fissures, long philtrum, micrognathia, and small C-shaped ears. Retinal exam demonstrated bilateral macular hypoplasia. At 5.5 months of age, the patient developed increased upper respiratory secretions with difficulty breathing; the patient died at home 2 weeks later. At autopsy, marked hypoplasia of all organs was noted, with hypomyelination of white matter and multiple renal cortical microcysts. Testes were high in the inguinal canals with no changes in the urogenital tract. Kariya et al. (2000) reported a boy with deletion of the short arm of chromosome 3 who had respiratory distress at birth and minor craniofacial anomalies, including long philtrum, thin lips, flat occiput, high broad forehead, hypertelorism, bilateral ptosis, upturned nose, high-arched palate, micrognathia, retrognathia, preauricular pit, and ear malformation. Despite good sucking, the patient exhibited a swallowing disturbance and was fed by nasogastric tube. Abdominal sonography and ophthalmologic and otoscopic examination were normal, as was CT scan of the temporal bone. Auditory brainstem evoked responses were absent at 1 month and 10 months of age, and he never showed any reaction to visual or auditory stimulation during his life. Brain imaging showed a hypoplastic corpus callosum and enlargement of the lateral ventricle. He had a severely abnormal EEG with low voltage and irregular wave pattern, and began having frequent seizures at the age of 6 months. Psychomotor retardation was observed. He died of kidney and heart failure with fever at 2 years of age.
In a boy with 3p- syndrome, Angeloni et al. (1999) found that the break was distal to the von Hippel-Lindau syndrome gene (VHL; 608537), removing marker D3S18 and the CALL gene (CHL1; 607416). The authors suggested that deletion ... In a boy with 3p- syndrome, Angeloni et al. (1999) found that the break was distal to the von Hippel-Lindau syndrome gene (VHL; 608537), removing marker D3S18 and the CALL gene (CHL1; 607416). The authors suggested that deletion of 1 copy of the CALL gene might be responsible for mental defects in patients with 3p- syndrome. Green et al. (2000) studied 10 individuals with chromosome 3pter-p25 deletions, 5 of whom had congenital heart disease. Congenital heart defects, typically AVSD (see AVSD2; 606217), occur in approximately one-third of individuals with 3p- syndrome (Phipps et al., 1994; Drumheller et al., 1996). Green et al. (2000) identified a susceptibility locus for AVSD in cytogenetic band 3p25, bounded by markers at D3S1263 and D3S3594, an interval of 3.7 cM. Cargile et al. (2002) stated that all reported cases of terminal 3p deletion involved, at a minimum, the loss of chromosomal material telomeric to 3p25.3. Cargile et al. (2002) defined a minimum candidate region conferring the common features of the syndrome by study of a patient with clinical findings consistent with terminal 3p deletion who had an interstitial deletion involving a 4.5-Mb interval between markers D3S3630 and D3S1304. Cargile et al. (2002) noted that the CALL gene was outside the area of deletion in this patient, but the ITPR1 gene (147265), encoding an intracellular calcium channel expressed in the brain, was located in the critical region and might be a good candidate gene for mental retardation. Endris et al. (2002) performed molecular analysis in a patient with a balanced de novo translocation t(X;3)(p11.2;p25), hypotonia, and severe mental retardation, features characteristic of 3p- syndrome. The translocation breakpoint on the X chromosome was located outside of any coding region; however, the breakpoint on chromosome 3 interrupted a previously unknown gene which Endris et al. (2002) designated MEGAP, 'mental disorder-associated GAP protein' (SRGAP3; 606525). Noting that MEGAP is highly expressed in fetal and adult brain tissue, Endris et al. (2002) suggested that the phenotype they observed in their patient was caused by misregulation of neuronal signal-transduction machinery controlling the correct migration of neurons and their axonal connectivity, and proposed that haploinsufficiency of MEGAP leads to the abnormal development of neuronal structures that are important for normal cognitive function. Fernandez et al. (2004) identified a boy with characteristic physical features of 3p deletion syndrome and both verbal and nonverbal developmental delay who carried a de novo balanced translocation t(3;10)(p26;q26). Fine mapping of this rearrangement demonstrated that the translocation breakpoint on chromosome 3 fell within the minimum candidate region for 3p deletion syndrome and disrupted the CNTN4 (607280) mRNA transcript at 3p26.3-p26.2. This transcript is a member of the immunoglobulin superfamily of neuronal cell adhesion molecules involved in axon growth, guidance, and fasciculation in the central nervous system (CNS). The results demonstrated the association of CNTN4 disruption with the 3p deletion syndrome phenotype and strongly suggested a causal relationship. In an addendum, the authors stated that the patient they described met clinical criteria for an autism spectrum disorder (see 209850), with impaired social functioning, language delay, and repetitive behaviors. Takagishi et al. (2006) analyzed a chromosome 3p25 deletion in a mother and daughter that had minimal phenotypic effect. The mother had only minor dysmorphism, including simple-formed ears, high-arched palate, fourth and fifth toe clinodactyly, and a history of moderate scoliosis that required bracing. Her daughter, examined at 15 months of age, had ears that were simple but normal in size, a 'somewhat high' palate, mild hypotonia with mild joint laxity, and fourth and fifth toe clinodactyly; she exhibited no developmental delay. Cytogenetic analysis revealed a terminal 3pter-p25.3 deletion in both mother and daughter. Takagishi et al. (2006) concluded that the 3p25 deletion syndrome might have a much broader phenotypic spectrum than previously recognized. Malmgren et al. (2007) performed fine mapping in 3 patients with distal 3p deletions, including the female patient originally reported by Ramer et al. (1989). The deletions ranged in size from 10.2 Mb to 11 Mb and encompassed 47 to 51 known genes, including VHL. The location of the proximal breakpoint in 1 of the patients suggested that the previously identified critical region for heart defects might be narrowed down to 0.45 Mb; Malmgren et al. (2007) also concluded that deletion of the ATP2B2 gene (108733) alone, previously suggested as a candidate for the hearing impairment in this syndrome, is not sufficient. Comparison with 9 previously characterized 3p deletion cases showed no common breakpoint. Malmgren et al. (2007) noted that most of the characteristic symptoms, such as growth retardation, feeding problems, hypotonia, microcephaly, and the very characteristic facial features, were present in almost all patients, including the 1 with the smallest interstitial deletion (Cargile et al., 2002). Shuib et al. (2009) analyzed 14 patients with cytogenetically detectable deletions of 3p25, 10 of whom had previously been reported (Green et al., 2000; Zatyka et al., 2005) and found that deletion size ranged from 6 to 12 Mb. Assuming complete penetrance, a candidate critical region for a congenital heart disease susceptibility gene was refined to approximately 200 kb, and a candidate critical region for mental retardation was mapped to an approximately 1-Mb interval containing the SRGAP3 gene but excluding other 3p neurodevelopmental genes including CHL1, CTN4, LRRN1, and ITPR1. Shuib et al. (2009) suggested that SRGAP3 is the major determinant of mental retardation in distal 3p deletions.