‘De novo’ trisomy 16q11→pter

Summary A de novo 16q- trisomy was found in a patient with severe mental retardation and mild physical abnormalities.A preliminary delineation the clinical features characteristic of trisomy 16q- is proposed, based upon comparison of the two cases identified so far. The mild phenotypical effects of this chromosome imbalance suggest that the alleged lethality of partial chromosome 16 aneuploidies should be reconsidered.     

A New Neurological Syndrome with Mental Retardation, Choreoathetosis, and Abnormal Behavior Maps to Chromosome Xp11

Choreoathetosis is a major clinical feature in only a small number of hereditary neurological disorders. We define a new X-linked syndrome with a unique clinical picture characterized by mild mental retardation, choreoathetosis, and abnormal behavior. We mapped the disease in a four-generation pedigree to chromosome Xp11 by linkage analysis and defined a candidate region containing a number of genes possibly involved in neuronal signaling, including a potassium channel gene and a neuronal G protein-coupled receptor.     

A new case of dup(1)(q21.2q12) in an individual with mild mental retardation

Proximal duplications of the long arm of chromosome 1 are rare and the few patients that have been described in literature have multiple congenital abnormalities and/or mental retardation. The present paper describes the clinical and cytogenetic findings of an adult patient with only mild mental retardation and some minor malformations. The patient carries an inverted duplication of 1q12q21.2.     

Segregation of FRAXE in a large family: clinical, psychometric, cytogenetic, and molecular data.

During an ongoing study on X-linked mental retardation, we ascertained a large family in which mild mental retardation was cosegregating with a fragile site at Xq27-28. Clinical, psychometric, cytogenetic, and molecular studies were performed. Apart from mild mental retardation, affected males and females did not show a specific clinical phenotype. Psychometric assessment of four representative affected individuals revealed low academic achievements, with verbal and performance IQs of 61-75 and 70-82, respectively. Cytogenetically the fragile site was always present in affected males and was not always present in affected females. With FISH the fragile site was located within the FRAXE region. The expanded GCC repeat of FRAXE was seen in affected males and females either as a discrete band or as a broad smear. No expansion was seen in unaffected males, whereas three unaffected females did have an enlarged GCC repeat. Maternal transmission of FRAXE may lead to expansion or contraction of the GCC repeat length, whereas in all cases of paternal transmission contraction was seen. In striking contrast to the situation in fragile X syndrome, affected males may have affected daughters. In addition, there appears to be no premutation of the FRAXE GCC repeat, since in the family studied here all males lacking the normal allele were found to be affected.     

Intellectual developmental disorders: towards a new name, definition and framework for "mental retardation/intellectual disability" in ICD-11

Although "intellectual disability" has widely replaced the term "mental retardation", the debate as to whether this entity should be conceptualized as a health condition or as a disability has intensified as the revision of the World Health Organization (WHO)'s International Classification of Diseases (ICD) advances. Defining intellectual disability as a health condition is central to retaining it in ICD, with significant implications for health policy and access to health services. This paper presents the consensus reached to date by the WHO ICD Working Group on the Classification of Intellectual Disabilities. Literature reviews were conducted and a mixed qualitative approach was followed in a series of meetings to produce consensus-based recommendations combining prior expert knowledge and available evidence. The Working Group proposes replacing mental retardation with intellectual developmental disorders, defined as "a group of developmental conditions characterized by significant impairment of cognitive functions, which are associated with limitations of learning, adaptive behaviour and skills". The Working Group further advises that intellectual developmental disorders be incorporated in the larger grouping (parent category) of neurodevelopmental disorders, that current subcategories based on clinical severity (i.e., mild, moderate, severe, profound) be continued, and that problem behaviours be removed from the core classification structure of intellectual developmental disorders and instead described as associated features.     

Microcephaly, microphthalmia, congenital cataract, with calcification of the basal ganglia: MCA/MR syndrome

We present a Hungarian girl with microcephaly, microphthalmia, congenital cataract, prominent nasal root, peaked nose, micrognathia with high arched palate, mild mental retardation, calcification of the basal ganglia and serology for the connatal infections. We suggest that our proband may be an allelic variant of COFS syndrome.     

Trisomy 13qter by tandem duplication 46, XX, dir dup 13 (q21 qter), 9qh+]

A tandem translocation of chromosome 13-46,XXdup13(q21 leads to qter)--occurred de novo in a patient with the following features: normal birthweight; early feeding difficulties; mild psychomotor retardation; low set hairline on the forehead; thick eyebrows; long, upturned eyelashes; pointed nose; micrognathia; large, flat, posteriorly rotated ears; multiple hemangiomata; normal hematological status. The hypothesis of an unequal crossing-over is discussed, as well as the possibility of constructing a phenotypic map of chromosome 13.     

Characterization of a de novo duplication of 11p14----p13, using fluorescent in situ hybridization and southern hybridization

A de novo 11p+ chromosome was found in a child with mild mental retardation but no other remarkable dysmorphic characteristics. Banding studies suggested a duplication of regions 11p13 and 11p14 or regions 11p14 and 11p15. Using fluorescent in situ hybridization and digital imaging microscopy, we mapped probe p32.1 (D11S16) to the proximal part of region 11p14 (11p14.1) and demonstrated duplication of this probe in our patient. Southern hybridization showed duplication of p32.1 and other probes located at 11p13 and 11p14, but the gene for alpha calcitonin (CALCA), located at 11p15, was not duplicated. The application of these techniques led to the identification of the duplication as dir dup(11)(pter----p13::p15.1----qter).     

Autosomal dominant piebaldism and mental retardation syndrome associated with a t(1;2) (p22.1;q36)

A syndrome of piebaldism and mild to moderate mental retardation was present in 3 sibs and their father. Besides, the disorder was segregating concordantly with a t(1;2) (p22.1;q36). It is concluded that the syndrome is due, either by gene breakage or dysfunction, to the translocation.     

Chromosome 7 short-arm interstitial deletion (p14)

Summary A 13-year-old girl presented with microcephaly, short and broad neck, low posterior hairline, congenital heart disease, limitation of joint movement, and mild mental retardation. Chromosomal analysis showed interstitial deletion of band p14 of the short arm of chromosome 7. The patient's physical and cytogenetic findings are compared with those of five other patients with 7p-deletions.     

Endocrine function and diagnostic problems in a prepubertal case of 48,XXYY

A five-year-old 48,XXYY boy with normal external genitalia, slight bone anomalies and mild mental retardation is described. An endocrine examination revealed normal values with the possible exception of a slight increase of the LH values and the LH response to LH-RH stimulation.     

Supernumerary chromosome der(22)t(11;22): Emanuel syndrome associates with novel features

Emanuel syndrome results from +der(22)t(11q23;22q11). Cleft palate, ear anomalies, heart defects, genital anomalies, hypotonia, and mental retardation are the main features of the syndrome. We report a nine-year-old boy with the t(11;22)(q23;q11) chromosome, transmitted in an unbalanced fashion from his mother, and originated in the maternal grandmother's meiosis. In addition to mental retardation, hypotonia, craniofacial anomalies, and cryptorchidism, he has novel findings such as, joint hyperextensibility, left liver lobe agenesis, left sided malposition of the gallbladder and pancreas hypoplasia. This is the first report associating these features with Emanuel syndrome.     

X-linked mental retardation with seizures and carrier manifestations is caused by a mutation in the creatine-transporter gene (SLC6A8) located in Xq28

A family with X-linked mental retardation characterized by severe mental retardation, speech and behavioral abnormalities, and seizures in affected male patients has been found to have a G1141C transversion in the creatine-transporter gene SLC6A8. This mutation results in a glycine being replaced by an arginine (G381R) and alternative splicing, since the G-->C transversion occurs at the -1 position of the 5' splice junction of intron 7. Two female relatives who are heterozygous for the SLC6A8 mutation also exhibit mild mental retardation with behavior and learning problems. Male patients with the mutation have highly elevated creatine in their urine and have decreased creatine uptake in fibroblasts, which reflects the deficiency in creatine transport. The ability to measure elevated creatine in urine makes it possible to diagnose SLC6A8 deficiency in male patients with mental retardation of unknown etiology.     

Familial mental retardation syndrome ATR-16 due to an inherited cryptic subtelomeric translocation, t(3;16)(q29;p13.3)

In the search for genetic causes of mental retardation, we have studied a five-generation family that includes 10 individuals in generations IV and V who are affected with mild-to-moderate mental retardation and mild, nonspecific dysmorphic features. The disease is inherited in a seemingly autosomal dominant fashion with reduced penetrance. The pedigree is unusual because of (1) its size and (2) the fact that individuals with the disease appear only in the last two generations, which is suggestive of anticipation. Standard clinical and laboratory screening protocols and extended cytogenetic analysis, including the use of high-resolution karyotyping and multiplex FISH (M-FISH), could not reveal the cause of the mental retardation. Therefore, a whole-genome scan was performed, by linkage analysis, with microsatellite markers. The phenotype was linked to chromosome 16p13.3, and, unexpectedly, a deletion of a part of 16pter was demonstrated in patients, similar to the deletion observed in patients with ATR-16 syndrome. Subsequent FISH analysis demonstrated that patients inherited a duplication of terminal 3q in addition to the deletion of 16p. FISH analysis of obligate carriers revealed that a balanced translocation between the terminal parts of 16p and 3q segregated in this family. This case reinforces the role of cryptic (cytogenetically invisible) subtelomeric translocations in mental retardation, which is estimated by others to be implicated in 5%-10% of cases.     

Renpenning syndrome maps to Xp11.

Mutations in genes on the X chromosome are believed to be responsible for the excess of males among individuals with mental retardation. Such genes are numerous, certainly >100, and cause both syndromal and nonsyndromal types of mental retardation. Clinical and molecular studies have been conducted on the Mennonite family with X-linked mental retardation (XLMR) reported, in 1962, by Renpenning et al. The clinical phenotype includes severe mental retardation, microcephaly, up-slanting palpebral fissures, small testes, and stature shorter than that of nonaffected males. Major malformations, neuromuscular abnormalities, and behavioral disturbances were not seen. Longevity is not impaired. Carrier females do not show heterozygote manifestations. The syndrome maps to Xp11.2-p11.4, with a maximum LOD score of 3.21 (recombination fraction 0) for markers between DXS1039 and DXS1068. Renpenning syndrome (also known as "MRXS8"; gene RENS1, MIM 309500) shares phenotypic manifestations with several other XLMR syndromes, notably the Sutherland-Haan syndrome. In none of these entities has the responsible gene been isolated; hence, the possibility that two or more of them may be allelic cannot be excluded at present.     

Two Down syndrome patients with rec(21),dupq,inv(21)(p11;q2109) from a familial pericentric inversion

Aneusomie de recombinaison arose from a familial pericentric inversion of a chromosome 21. Two female patients had a typical Down syndrome; one of them had slight psychomotor retardation. There was partial trisomy 21q2109----qter in these two patients but ZnCu SOD activity was normal.     

Trisomy 11 q (q23.1 - qter) through maternal translocation t(11;22) (q23.1;q11.1). A new case]

A 4-year-old boy with partial trisomy 11q resulting from malsegregation of a maternal translocation, t(11;22)(q23.1;q11.1), exhibits the following malformations: severe mental deficiency; growth retardation and hypotonia; brachycephaly with flattened occiput and forehead; facial dysmorphia; pre-auricular fistula. These features are in good agreement with the syndrome recently described for partial trisomy 11q. The translocation appears to be identical in that in three other families already reported.     

Trisomy 20pter»q11 in a malformed boy from a t(13;20)(p11;q11) translocation-carrier mother

Summary A 31-year-old boy revealed moderate motor and mental retardation, normal growth, a congenital heart defect and multiple minor dysmorphic signs and anomalies including brachycephaly, orbital hypotelorism, upward slanting palpebral fissures, short and beaked nose, full cheeks, malformed auricles, hypoplastic external genitalia, rocker-bottom feet with prominent heels, and various minor radiologic anomalies of bones. An extra chromosome in his karyotype appeared to represent trisomy of the short arm of chromosome 20 due to a maternally inherited balanced t(13;20)(p11;q11) translocation.     

Radiographic, histologic, and cytologic lesions associated with mutations in the fitness1(4226SB) locus of mice.

BACKGROUND AND PURPOSE: Previous investigation of fitness1(4226SB) mice revealed growth retardation and microcytic, hypochromic anemia with functional iron deficiency. Serum biochemical analysis suggested protein-losing enteropathy and liver dysfunction. METHODS: Radiography was done to assess lumbar bone lesions in mice hemizygous for fitness1 (fit1) [c fit1(4226SB/Df(c Mod2 sh1)26DVT] and age-matched sibling controls [c(ch)+/c(ch)+] at 40 or 60 days of age. Macroscopic and microscopic lesions were evaluated at necropsy. Bone marrow was examined cytologically to evaluate hematopoietic lesions. RESULTS: Mice hemizygous for fit1 had radiographically evident lumbar vertebral abnormalities, including various degrees of vertebral body fusion, with loss of intervertebral disk spaces and mild, generalized osteopenia. All mutant mice had scoliosis. Several mutant mice had lordosis and/or kyphosis of variable severity and mild subluxation at the lumbosacral junction. Marked splenomegaly and mild cardiomegaly were evident, and bone marrow color ranged from normal to slightly pale. The spleen had marked extramedullary hematopoiesis; lumbar vertebrae contained microscopic lesions that corresponded to the radiographic lesions. Cytologic examination of bone marrow revealed normocellular to hypocellular status, with mild to moderate erythroid hypoplasia characterized by mild increase in the myeloid-to-erythroid cell ratio, decreased percentage of erythroid precursors, and slight increase in percentage of myeloid precursor cells. CONCLUSIONS: Mutations in fit1 directly or indirectly cause alteration(s) in blood, organs of hematopoiesis (bone marrow, spleen, and liver), heart, and vertebral column, and suggest that this mouse may be a good model for study of scoliosis and relationships between iron metabolism and bone growth.